REMS: FDAs Application of 
Statutory Factors in 
Determining When a REMS Is 
Necessary 
 
Guidance for Industry
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2019 
Drug Safety 
   
   
 
REMS: FDAs Application of 
Statutory Factors in 
Determining When a REMS Is 
Necessary 
 
Guidance for Industry
 
 
 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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Email:  druginfo@fda.hhs.gov 
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and/or 
 
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Email:  ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2019 
Drug Safety
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  MANAGING DRUG RISKS ............................................................................................ 4 
IV.   THE USE OF REMS IN MANAGING DRUG RISKS ................................................. 4 
V.  APPLICATION OF STATUTORY FACTORS IN REMS DECISION-MAKING... 5 
A.  Seriousness of Known or Potential Adverse Events That May Be Related to the 
Drug and the Background Incidence of Such Events in the Population Likely To Use 
the Drug ............................................................................................................................. 6 
B.  Expected Benefit of the Drug With Respect to the Disease or Condition .................... 7 
C.  Seriousness of the Disease or Condition To Be Treated ............................................... 8 
D.  Whether the Drug Is a New Molecular Entity ............................................................... 8 
E.  Expected or Actual Duration of Treatment With the Drug .......................................... 9 
F.  Estimated Size of Population Likely To Use the Drug .................................................. 9 
VI.  ADDITIONAL CONSIDERATIONS: POTENTIAL BURDEN ON THE HEALTH 
CARE DELIVERY SYSTEM AND PATIENT ACCESS ............................................ 9 
 
  Contains Nonbinding Recommendations 
 
REMS: FDAs Application of Statutory Factors in Determining 
When a REMS Is Necessary 
 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to clarify how the Food and Drug Administration (FDA or Agency) 
applies the factors set forth in section 505-1 of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 355-1) in determining whether a risk evaluation and mitigation strategy 
(REMS) is necessary to ensure that the benefits of a drug outweigh its risks.2  This guidance 
fulfills one of the performance goals that FDA agreed to satisfy in the reauthorization of the 
Prescription Drug User Fee Act (PDUFA) V.3   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in agency guidances means that something is suggested or 
recommended, but not required. 
 
 
                                                 
1 This guidance has been prepared by the Office of New Drugs, Office of Surveillance and Epidemiology, Office of 
Medical Policy, and Office of Regulatory Policy in the Center for Drug Evaluation and Research (CDER), in 
cooperation with the Center for Biologics Evaluation and Research (CBER), at the Food and Drug Administration.  
2 Section 505-1 of the FD&C Act applies to applications for prescription drugs submitted or approved under 
subsections 505(b) (i.e., new drug applications) or (j) (i.e., abbreviated new drug applications) of the FD&C Act and 
to applications submitted or licensed under section 351 (i.e., biologics license applications) of the Public Health 
Service Act (PHS Act) (42 U.S.C. 262).  For the purposes of this document, unless otherwise specified, the term 
drug refers to human prescription drugs, including those that are licensed as biological products (biologics). 
3 Section XI.A.1 of PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017 
(PDUFA V), available at 
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf.  
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
The Food and Drug Administration Amendments Act of 2007 (FDAAA)4 created section 505-1 
of the FD&C Act, which establishes FDAs REMS authority.  A REMS is a required risk 
management plan that can include one or more elements to ensure that the benefits of a drug 
outweigh its risks.5    
 
If FDA determines that a REMS is necessary, the Agency may require one or more REMS 
elements, which could include a Medication Guide,6 a patient package insert,7 and/or a 
communication plan.8  FDA may also require elements to assure safe use (ETASU) as part of a 
REMS.9  ETASU may be required if the drug has been shown to be effective, but is associated 
with a specific serious risk and can be approved only if, or would be withdrawn unless, such 
elements are required as part of a strategy to mitigate a specific serious risk(s) listed in the 
labeling of the drug.  ETASU may be required for approved drug products that were initially 
approved without ETASU when other elements are not sufficient to mitigate a serious risk.  
Specifically, ETASU may include one or any combination of the following requirements10: 
  Health care providers who prescribe the drug have particular training or experience, or 
are specially certified; 
  Pharmacies, practitioners, or health care settings that dispense the drug are specially 
certified; 
  The drug be dispensed to patients only in certain health care settings, such as hospitals; 
  The drug be dispensed to patients with evidence or other documentation of safe use 
conditions, such as laboratory test results; 
  Each patient using the drug be subject to monitoring; or 
  Each patient using the drug be enrolled in a registry. 
 
If a REMS includes certain ETASU, the REMS may also include an implementation system to 
enable the applicant to monitor, evaluate, and improve the implementation of the elements (e.g., 
development of a REMS specific Web site or call center to facilitate enrollment; establishment of 
electronic databases of certified health care settings).11 
                                                 
4 Public Law 110-85.  
5 See section 505-1(e) of the FD&C Act and section 505-1(f) of the FD&C Act. 
6 See Section 505-1(e)(2) of the FD&C Act. 
7 Id. 
8 See Section 505-1(e)(3) of the FD&C Act. 
9 See Section 505-1(f) of the FD&C Act. 
10 See Section 505-1(f)(3) of the FD&C Act. 
 
11 See Section 505-1(f)(4) of the FD&C Act. 
 
 
2  Contains Nonbinding Recommendations 
 
All REMS should include one or more overall goals, and if the REMS has ETASU, the REMS 
must include one or more goals to mitigate a specific serious risk listed in the labeling of the 
drug and for which the ETASU are required.12   
Finally, REMS generally must include a timetable for submission of assessments of the REMS.13  
The timetable for submission of assessments of the REMS must include an assessment by the 
dates that are 18 months and 3 years after the REMS is initially approved, and an assessment in 
the 7th year after the REMS is approved, or at another frequency specified in the REMS.14 
FDA can require a REMS before initial approval of a new drug application or, should FDA 
become aware of new safety information15 about a drug and determine that a REMS is necessary 
to ensure that the benefits of the drug outweigh its risks, after the drug has been approved.16 
 
Before FDAAA was enacted, FDA approved a small number of drugs and biologics with risk 
minimization action plans (RiskMAPs).17  A RiskMAP is a strategic safety program designed to 
meet specific goals and objectives in minimizing the known risks of a drug while preserving the 
drugs benefits.  RiskMAPs were developed for products that had risks that required additional 
risk management strategies that went beyond the provision of FDA-approved labeling, including 
the prescribing information.18  In 2005, FDA issued a guidance for industry, Development and 
Use of Risk Minimization Action Plans (RiskMAP Guidance).19 Many of the principles described 
in the RiskMAP Guidance are reflected in the REMS provisions set forth in FDAAA20 and have 
been incorporated into FDAs REMS decision-making process.  The purpose of this new 
guidance is to explain FDAs current application of previously articulated risk management 
principles and considerations under the REMS regulatory paradigm. 
 
  
                                                 
12 See Section 505-1(f)(3) of the FD& C Act. 
13 New Drug Applications (NDAs) and Biologics License Applications (BLAs) must include a timetable for 
submission of assessments. ANDAs are not subject to the requirement for a timetable for submission of assessments 
(Section 505-1(i)), but FDA can require any application holder, including ANDA applicants, to submit REMS 
assessments under Section 505-1(g)(2)(C). 
14 See Section 505-1(d); see also 505-1(g)(2) of the FD&C Act. 
15 Section 505-1(b)(3) of the FD&C Act. 
16 See section 505-1(a)(2) of the FD&C Act. 
17 Some of these drugs were approved pursuant to either subpart H (21 CFR 314.520) or subpart E (21 CFR 601.42) 
with restrictions on their use or distribution to assure safe use. 
18 A drugs prescribing information (PI) contains a summary of the essential scientific information needed for the 
safe and effective use of the drug.  21 CFR 201.56(a)(1).   The PI is updated from time to time to incorporate 
information from postmarketing surveillance or studies, for example, revealing new benefits or risk concerns. 
19 The RiskMAP Guidance is available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm071616.pdf. 
20 See section 505-1(a)(1) of the FD&C Act. 
3  Contains Nonbinding Recommendations 
 
III.  MANAGING DRUG RISKS 
 
The statutory standard for FDA approval of a drug is that the drug is safe and effective for its 
labeled indications under its labeled conditions of use.21  FDAs determination that a drug is 
safe, however, does not suggest an absence of risk.  Rather, a drug is considered to be safe if the 
clinical significance and probability of its beneficial effects outweigh the likelihood and medical 
importance of its harmful or undesirable effects.  In other words, a drug is considered safe if it 
has an appropriate benefit-risk balance. 
 
Risk management is a key factor in FDAs risk-benefit assessment.22  As described in previous 
guidances, risk management consists of both risk assessment and risk minimization: it is an 
iterative process involving (1) assessing a drugs benefit-risk balance, (2) developing and 
implementing tools to minimize the drugs risks while preserving its benefits, (3) evaluating tool 
effectiveness and reassessing the benefit-risk balance, and (4) making adjustments, as 
appropriate, to risk minimization tools to further improve the benefit-risk balance.  This four-part 
process should be continuous throughout a drugs life cycle, with the results of risk assessment 
informing the sponsors decisions regarding risk minimization.23 
 
 
IV.   THE USE OF REMS IN MANAGING DRUG RISKS 
 
The goal of risk mitigation is to preserve a drugs benefits while reducing its risks to the extent 
possible.  For the majority of drugs, routine risk mitigation measures, such as providing health 
care providers with risk information through FDA-approved prescribing information, are 
sufficient to preserve benefits while minimizing risks.  In some cases, however, FDA may 
consider whether a REMS would help ensure that the benefits of the drug outweigh its risks. 
 
FDAs determination as to whether a REMS is necessary for a particular drug is a complex, 
drug-specific inquiry, reflecting an analysis of multiple, interrelated factors and of how those 
factors apply in a particular case.  In conducting this analysis, FDA considers whether (based on 
premarketing or postmarketing risk assessments) there is a particular risk or risks associated with 
the use of the drug that, on balance, outweigh its benefits and whether additional interventions 
beyond FDA-approved labeling are necessary to ensure that the drugs benefits outweigh its 
risks.  
 
In making these determinations, FDA may take into consideration information from a variety of 
sources, including FDAs internal and external experts with specialized expertise relevant to a 
particular risk, input on relevant issues from other centers within FDA, other government 
                                                 
21 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)). 
22 Information about FDAs Benefit-Risk Assessment Framework is available at 
https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm 
 
23 See the following FDA guidances for industry: Premarketing Risk Assessment, available at 
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm072002.pdf; 
RiskMAP Guidance; and Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, available at 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm071696.pdf. 
 
4  Contains Nonbinding Recommendations 
 
agencies, advisory committee meetings, the Drug Safety Oversight Board, literature, and 
professional societies.  For approved drugs, FDA may also gather information from post-
approval adverse event reports and active surveillance, as well as from post-approval clinical 
trials and other post-approval studies, including epidemiological studies, when evaluating 
whether a REMS is necessary. 
 
If FDA determines that a REMS is necessary, the Agency considers what the goals of a proposed 
REMS to address these risks would be and what specific REMS elements, as described above, 
could help meet those goals.  The REMS should be designed to meet the relevant goals, not 
unduly impede patient access to the drug, and minimize the burden on the health care delivery 
system to the extent practicable.  If FDA believes that the drugs risks would exceed its benefits 
even if FDA were to require a REMS for the drug, FDA will not approve the drug or may 
consider seeking withdrawal of the drug if it is already being marketed.   
 
 
V.  APPLICATION OF STATUTORY FACTORS IN REMS DECISION-MAKING 
 
Section 505-1(a)(1) of the FD&C Act, as added by FDAAA, requires FDA to consider the 
following six factors24 in making a decision about whether to require a REMS:  
 
  The seriousness of any known or potential adverse events that may be related to the drug 
and the background incidence of such events in the population likely to use the drug;  
 
  The expected benefit of the drug with respect to the disease or condition; 
 
  The seriousness of the disease or condition that is to be treated with the drug; 
 
  Whether the drug is a new molecular entity;  
 
  The expected or actual duration of treatment with the drug; and 
 
  The estimated size of the population likely to use the drug.  
 
These six factors influence FDAs decisions with respect to whether a REMS is required for a 
particular drug and what type of REMS might be necessary (i.e., what specific elements or tools 
should be included as part of the REMS).  FDA makes decisions about requiring a REMS as part 
of a benefit-risk determination for a drug after an evaluation that includes integrated 
consideration of each of the statutory factors.  All six factors are considered together to inform 
FDAs REMS decision making process and no single factor is determinative as to whether a 
REMS is necessary.  The relative importance or weight of each factor is a case specific inquiry.  
The application of these factors is discussed in the sections below. 
 
                                                 
24 The FD&C Act requires that FDA consider these factors in determining whether a REMS is necessary for a new 
drug.  FDA also generally considers these factors in determining whether (based on new safety information) a 
REMS is necessary for a drug that is the subject of an approved application. 
5  Contains Nonbinding Recommendations 
 
A.  Seriousness of Known or Potential Adverse Events That May Be Related to 
the Drug and the Background Incidence of Such Events in the Population 
Likely To Use the Drug 
 
The more serious25 a drugs known or potential associated risks relative to its benefits, the more 
likely it is that a REMS will be necessary to ensure that the benefits of the drug outweigh its 
risks. In determining whether to require a REMS, FDA considers the source, nature and 
reliability of available scientific evidence about the adverse events as well as the characteristics 
of the risks, including the reversibility, preventability, temporality, frequency, severity, 
background incidence, and likelihood of occurrence.  
 
For drugs associated with adverse events that are reversible or preventable if particular measures 
are taken promptly, FDA may consider requiring a REMS to help ensure that such measures are 
undertaken in a timely manner to minimize or prevent a serious adverse event.  For example, for 
a drug that is associated with hepatotoxicity that is reversible with drug discontinuation, the 
REMS may require that the patient be monitored through laboratory studies so that the drug can 
be discontinued if and when hepatic enzyme elevations are observed.  
 
A drug that is associated with a risk of a serious adverse event that is irreversible, such as one 
that causes a permanent disability or persistent incapacity, may be particularly likely to have a 
favorable benefit-risk profile only in the presence of a REMS that helps minimize drug exposure 
and the associated occurrence of the adverse event.  In such cases, a REMS may include, for 
example, a prescriber certification requirement that includes prescriber training and patient 
counseling on the nature of the associated risk and on the drugs benefit-risk balance to facilitate 
informed patient and prescriber decisions about treatment with the drug.  Such REMS are 
designed to ensure that patients are fully informed of the serious risk before beginning therapy 
and may involve patient acknowledgment forms or other methods of documenting that such 
patient-provider discussions have taken place.  This kind of REMS is particularly important for 
drugs with limited available methods of preventing the actual occurrence of drug-associated 
adverse events.   
 
The frequency and severity of adverse events associated with the use of a drug may also affect 
FDAs determination of whether a REMS is necessary.  While a high frequency of adverse 
events may necessitate a REMS to mitigate this risk, FDA may also require a REMS for an 
infrequent adverse event, if the adverse event is particularly severe.   
 
As part of its assessment of whether a particular adverse event is drug-associated, FDA examines 
the rate of the adverse event in individuals exposed to the drug relative to the background 
incidence of the adverse event in the population likely to use the drug.  If an adverse event is 
determined to be drug-associated, FDA may determine that treatment with the drug unacceptably 
                                                 
25 Section 505-1(b)(4) of the FD&C Act defines an adverse drug experience as serious if it results in death, 
immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect (or, based on appropriate medical judgment, may jeopardize the patient and may require a 
medical or surgical intervention to prevent the above-described outcomes). 
6  Contains Nonbinding Recommendations 
 
increases the frequency and/or severity of the adverse event in the patient population and that 
this risk needs to be mitigated through a REMS.   
 
As part of its evaluation of the risks associated with the use of a drug, FDA also takes into 
consideration whether information about managing the particular risk is widely available and 
whether risk management measures are being widely implemented.  FDA may also consider 
factors such as the specialties of the healthcare providers who may prescribe, dispense or 
administer the drug and whether approaches to mitigate the risk are standard and well-known by 
the health care professional or are less familiar to the health care professional when determining 
whether a REMS is needed. The Agency also takes into account the health care setting(s) in 
which the drug is used or is likely to be used. For drugs intended for use in an outpatient setting, 
FDA considers the degree to which patients can be expected to reliably recognize symptoms as 
being associated with a drug and to take necessary actions to address adverse events.  If, for 
example, FDA expects that a drug will likely be used in a setting where patient monitoring and 
certain medical equipment are not available, and believes that such measures are needed to 
mitigate the risks associated with the use of the drug, FDA may require a REMS with ETASU to 
limit use of the drug to settings in which these measures are available.   
 
B.  Expected Benefit of the Drug With Respect to the Disease or Condition  
  
When assessing a drugs expected benefits with respect to a specific disease or condition, FDA 
may evaluate information about the drugs effectiveness, whether the drug treats a serious 
disease or condition, whether it fills an unmet medical need, and whether it can cure the disease 
or alleviate its symptoms.  FDA may also consider the extent to which new dosage forms 
enhance convenience of administration and/or improve adherence to prescribed regimens, and 
whether new formulations or delivery mechanisms may extend treatment to patient populations 
who were formerly unable to use the drug.   
 
A drugs expected benefits, however, are not considered in isolation.  In determining whether a 
REMS is necessary, FDAs assessment of a drugs benefit is balanced against consideration of 
the risks associated with its use.  For example, a once-a-month oral dosage form of a drug that 
was previously only available as a daily oral dosage form may offer a meaningful benefit in 
terms of convenience to the patient and adherence to medication therapy, but may have a 
different risk profile (e.g., a new risk associated with the new formulation, or with the longer 
half-life of the drug) that makes it more likely that FDA would determine that a REMS is 
necessary to ensure that the benefits of the drug outweigh its risks.  
 
7  Contains Nonbinding Recommendations 
 
C.  Seriousness of the Disease or Condition To Be Treated  
 
The seriousness of the disease or condition26 to be treated is a part of FDAs overall analysis of 
the benefits of a drug:  the more serious the disease or condition to be treated, the greater the 
potential benefit of the drugs measured effect in the benefit-risk assessment.  Nevertheless, even 
for drugs intended to treat serious or life-threatening diseases or conditions, the severity, 
irreversibility, or duration of an associated risk may weigh in favor of a REMS.  For example, if 
a drug indicated for long-term treatment of an indolent, asymptomatic, or slowly progressing 
cancer also has a more immediate risk of serious and potentially fatal cardiac arrhythmias, FDA 
may conclude that, without a REMS, the risk of serious cardiac arrhythmias outweighs the 
potential benefits of this kind of cancer treatment.  In this example, a REMS may be required to 
educate prescribers about the risk, appropriate monitoring, and management of cardiac 
arrhythmias to help minimize the occurrence of the adverse event associated with the drug. 
 
D.  Whether the Drug Is a New Molecular Entity 
 
For new molecular entities (NMEs)27 and certain Biologics License Applications (BLAs) 
licensed under section 351(a) of the PHS Act, available information about the drug can be 
limited and, as a result, there may be greater uncertainty about risks associated with the use of 
the drug that might emerge in the post-approval setting.  When available safety information 
about a NME or BLA indicates a serious risk, there may be uncertainties about the nature of the 
serious risk (e.g., the strength of the association of the adverse event with drug treatment, the 
likelihood of occurrence of the adverse event, or the accuracy and/or reliability of the data).  
Depending on the nature of the uncertainties about the risks associated with the use of the drug, 
FDA may require a REMS to help ensure that the benefits of the drug outweigh its risks. 
 
                                                 
26 FDA has defined serious disease or condition as  
a disease or condition associated with morbidity that has substantial impact on day-to-day 
functioning.  Short-lived and self-limiting morbidity will usually not be sufficient, but the 
morbidity need not be irreversible, provided it is persistent or recurrent.  Whether a disease or 
condition is serious is a matter of clinical judgment, based on its impact on such factors as 
survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress 
from a less severe condition to a more serious one.  
(21 CFR 312.300(b)); see also FDAs guidance for industry on Expedited Programs for Serious Conditions  Drugs 
and Biologics, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf.  
27 FDA has defined the term new molecular entity as an active ingredient that contains no active moiety that has 
been previously approved by the Agency in an application submitted under section 505 of the Act (in any 
application approved or deemed approved from 1938 to the present), or has been previously marketed as a drug in 
the United States. See Manual of Policies and Procedures (MAPP) 5018.2 NDA Classification Codes, available at 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProce
dures/default.htm 
 
8  Contains Nonbinding Recommendations 
 
E.  Expected or Actual Duration of Treatment With the Drug 
 
The duration of treatment with a drug and the impact of treatment length on the likelihood and 
severity of adverse events also affect FDAs decision-making with regard to the need for a 
REMS.  If long-term therapy with a drug appears to increase the likelihood of a serious adverse 
event, FDA may require a REMS either to limit the duration of treatment or to ensure that 
patients on long term treatment are monitored, e.g., for liver function if the drug is associated 
with liver toxicity.  
 
A REMS may also be required for a drug with a relatively short duration of treatment, depending 
on the nature of the associated risk if, for example, the drug is associated with a serious adverse 
event that occurs immediately after administration.  Such a REMS may require that the drug only 
be administered in a setting in which monitoring is available to ensure that the adverse event can 
be appropriately managed or in a setting in which, for example, providers have received 
particular risk management training.  Similarly, a REMS may be required for a drug that is only 
intended to be administered once or twice if FDA determines that specialized training is 
necessary to prevent the occurrence of an adverse event associated with improper drug 
administration.  In some cases, serious adverse events may occur even after treatment with a 
drug has ended.  In such cases, FDA may determine that a REMS is required to ensure proper 
monitoring of patients for a period of time following completion of treatment.    
 
F.  Estimated Size of Population Likely To Use the Drug 
 
In considering the estimated size of the population likely to use the drug, FDA considers, among 
other things, the extent to which that population includes patients expected to use the drug for 
unapproved uses and the risks associated with those uses. In certain cases, FDA may consider 
whether a REMS designed to help ensure that a drugs use is limited to its approved indications 
is appropriate.    
 
 
VI.  ADDITIONAL CONSIDERATIONS: POTENTIAL BURDEN ON THE HEALTH 
CARE DELIVERY SYSTEM AND PATIENT ACCESS 
 
FDA understands that REMS, particularly those with ETASU, may impose some measure of 
burden on patients and/or health care providers.  When considering this burden on patient access 
and the health care delivery system, FDA takes into account existing REMS elements for other 
drugs with similar risks and whether the REMS under consideration can be designed to be 
compatible with established medical drug distribution, procurement, and dispensing systems.  
FDA also considers how patients for whom the drug is indicated currently access health care 
(such as whether patients are in rural or medically underserved areas) and whether the REMS 
may impose additional access difficulties.  FDA also takes into account the consequences of 
potential treatment interruption or delays, particularly where patients have serious or life-
threatening conditions and/or have difficulty accessing health care.  In such circumstances, FDA 
takes steps, to ensure that REMS are designed to minimize delays or interruptions in drug 
therapy that may have untoward clinical impact. Particularly for a REMS that requires additional 
procedures and controls in the patient care process, FDA also considers  the characteristics, 
9  Contains Nonbinding Recommendations 
 
experience, and size of the likely prescriber population; how the drug will likely be dispensed in 
the setting in which it will likely be used; and the patient population likely to use the drug.   
 
The selection of REMS elements and tools may be influenced by the extent to which they have 
already been used in the clinical trials to evaluate the drugs safety and efficacy, and by what is 
known about the effectiveness of the elements and tools more generally.  Selection of risk 
management elements and tools is also informed by any regulatory precedent for addressing 
similar risks.28 For example, if a serious risk is common to all members of a drug class, FDA 
will consider, as appropriate, how the Agency has previously managed the riskand seek 
opportunities to standardize the approach to managing that risk.  FDA also encourages sponsors 
to submit REMS proposals that are compatible with established distribution, procurement, and 
dispensing systems.  Following approval of a REMS, FDA continues to evaluate the impact of 
the REMS on patient access and the health care delivery system.  
                                                 
28 In addition, the elements and tools may be driven by results of previous REMS assessments for REMS designed 
to address a similar risk, a similar patient population, or a similar drug distribution or dispensing system to the 
product under review.     
10