This guidance is intended to help applicants
and reviewers in drafting the ADVERSE REACTIONS section of
prescription drug labeling as required by 21 CFR 201.57(c)(7). Its
primary purpose is to aid in (1) selecting information for inclusion
in the section, (2) characterizing adverse reactions selected for
inclusion, (3) organizing and presenting the information within the
section, and (4) updating adverse reaction information. The goal of
this guidance is to assist applicants in designing ADVERSE REACTIONS
sections that contain the drug safety information important to
patient management decisions and that convey the information in a
clear and accessible format.
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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.
As this guidance seeks to bring greater
consistency to the content and format of the ADVERSE REACTIONS
section, the Agency emphasizes that reviewer and applicant judgment
remain critical in assessing how or whether to present information
on an adverse reaction. FDA reviewers and applicants should assess
such factors as seriousness, severity, frequency, and strength of
causal association in determining which adverse reactions to include
in the ADVERSE REACTIONS section and in characterizing those
reactions. In general, the ADVERSE REACTIONS section includes only
information that would be useful to health care practitioners making
treatment decisions and monitoring and advising patients.
Exhaustive lists of every reported adverse event, including those
that are infrequent and minor, commonly observed in the absence of
drug therapy or not plausibly related to drug therapy should be
avoided (see § 201.57(c)(7) and the Glossary at the end of this
guidance for a definition of Adverse Reaction). Such lists are not
informative and tend to obscure the more clinically meaningful
information.
The ADVERSE REACTIONS section is required to
list the adverse reactions that occur with the drug and with drugs
in the same pharmacologically active and chemically related class,
if applicable (§ 201.57(c)(7)(i)). Separate lists are required for
adverse reactions identified from clinical trials (§ 201.57(c)(7)(ii)(A))
and those identified from spontaneous reports after a drug has been
marketed (§ 201.57(c)(7)(ii)(B)). This section of the guidance
provides recommendations for ensuring that information about the
most clinically important adverse reactions is readily accessible
(see III.A), and for organizing the information on adverse reactions
from clinical trials (see III.B) and from postmarketing safety
reports (see III.C).
Typically, adverse
reactions for a given drug will have varying clinical significance
(ranging from serious to minor) and certain adverse reactions that
have relatively serious clinical implications will be discussed,
often in greater detail, in other sections of labeling (e.g.,
WARNINGS AND PRECAUTIONS, CONTRAINDICATIONS, and BOXED WARNING).
The ADVERSE REACTIONS section should make it easier for health care
practitioners to recognize and retain the adverse reactions
information that is most important to prescribing decisions. The
beginning of the ADVERSE REACTIONS section should identify the most
clinically significant adverse reactions and direct practitioners to
more detailed information about those reactions, if any. For
example, the section should first:
·
Identify and cross-reference all
serious and otherwise important adverse reactions described in
greater detail in other labeling sections, especially BOXED
WARNING or WARNINGS AND PRECAUTIONS (e.g., see WARNINGS AND PRECAUTIONS
(5.1)).
·
Identify the most commonly occurring adverse reactions
(e.g., all adverse reactions occurring at a rate of 10 percent or
greater in the treatment group and at a rate at least twice the
placebo rate).
·
Identify adverse reactions, if any, that resulted in a
significant rate of discontinuation or other clinical intervention
(e.g., dosage adjustment, need for other therapy to treat an adverse
reaction) in clinical trials.
The presentation of
adverse reactions identified from clinical trials is the major
component of the ADVERSE REACTIONS section. The ADVERSE REACTIONS
section must include a listing of all such reactions that occurred
at or above a specified rate that is appropriate to the drug’s
safety database (see III.B.3), a separate listing of those adverse
reactions that occurred below the specified rate, but for which
there is some basis to believe there is a causal relationship
between the drug and the event (see III.B.4), and, to the extent
information is available and relevant, additional detail about the
nature, frequency, severity, duration, dose-response, and
demographic characteristics of those adverse reactions with
significant clinical implications (§ 201.57(c)(7)(ii)(A)). The
following is the recommended organization of adverse reactions
identified from clinical trials.
1. Description of Data Sources
The presentation of
adverse reactions information identified from clinical trials must
be preceded by information necessary to interpret the adverse
reactions
(§ 201.57(c)(7)(i)).
This information would ordinarily include a description of the
overall clinical trial database from which adverse reaction data
have been drawn, including a discussion of overall exposure (number
of patients, dose, schedule, duration), demographics of the exposed
population, designs of the trials in which exposure occurred (e.g.,
placebo-controlled, active-controlled), and any critical exclusions
from the safety database.
Sample Database Description
The data described below reflect exposure
to drug X in [n]
patients, including [n] exposed for 6 months and [n] exposed for
greater than one year. Drug X was studied primarily in placebo- and
active-controlled trials (n = __, and n = ___, respectively), and in
long-term follow up studies. The population was [age range],
[gender distribution], [race distribution] and had
[diseases/conditions]. Most patients received doses [describe
range, route of administration, frequency, duration, as
appropriate].
2. Statement on the Significance of Adverse Reaction Data
Obtained From Clinical Trials
To help place in
perspective the significance of adverse reaction data obtained
from clinical trials, the following statement, or an appropriate
modification, should precede the presentation of adverse reactions
from clinical trials:
Because clinical trials are conducted under
widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates
observed in practice.
3. Presentation of Common
Adverse Reactions (the Adverse Reactions Table)
The ADVERSE REACTIONS
section next should list the adverse reactions identified from
clinical trials that occurred at or above a specified rate
appropriate to the database (for purposes of this guidance, “common”
adverse reactions). The listing must include the rate of occurrence
of an adverse reaction for the drug and any comparators (active- or
placebo-controls), unless such data cannot be determined or
presenting the rates for a comparator would be misleading (§
201.57(c)(7)(ii)(A)). To permit side-by-side comparison of adverse
reaction rates, common adverse reactions are typically presented in
a table.
a.
Use Best Available Data
The data in the
listing of common adverse reactions should be derived from
placebo-controlled and/or dose-response studies if these data are
available and the databases are sufficiently large to be
informative. If these data are unavailable or not sufficiently
informative, the primary table should be based on active-controlled
data. If concurrently controlled data are unavailable, overall
rates from well-monitored, single-arm databases can be used to
provide some indication of what was observed in treated patients.
In general, only the most informative data should be presented in
the table. For example, if placebo-controlled data were available
and sufficiently informative, there would usually be no need to
present in a table active-controlled data, single-arm trial data, or
the overall safety data, even if they are from larger databases. If
a data source is not used in the development of a table, but
provides important information about adverse reactions listed in the
table that is not found in the trials used in the development of the
table (e.g., information about prolonged duration of therapy), that
information can be discussed in the commentary following the table
(see III.B.5).
b.
Description of Data Sources for the Table
The table should be accompanied by a
description of the data sources reflected in the table, the basis
for including adverse reactions in the table (e.g., all reactions
occurring at > n% in the treated group and for which the rate for
drug exceeds the rate for placebo), and the way in which adverse
reaction rates were derived (e.g., for a given adverse reaction, was
the rate derived from all reported adverse events of that type not
present at baseline or from a subset of reported events deemed by
investigators to be drug-related). The description of data sources
should indicate the types of studies from which the information in
the table was derived and whether the study data were pooled. This
information can be provided in text preceding the table, in a
footnote to the table, in the title to the table, or some
combination of these.
c. How Many
Tables?
A single
adverse reaction table will usually be adequate. However, it may be
more informative to present data in more than one table when a
drug’s adverse reaction profile differs substantially from one
setting or population to another, the adverse reactions that differ
are clearly drug related, and the data have important implications
for use (or nonuse) and monitoring. Situations in which there may
be important differences between rates include different
indications, formulations, demographic subgroups, study durations,
dosing regimens, and types of studies (e.g., intensely monitored
small studies vs. a large outcome study). In these situations, the
content of the additional table or tables should be limited to only
those adverse reactions for which there were meaningful differences
in rates.
4. Presentation of Less Common
Adverse Reactions
The ADVERSE REACTIONS
section next should present those adverse reactions that occurred
below the specified rate for inclusion in the common adverse
reactions table or listing, but for which there is some basis to
believe there is a causal relationship between the drug and the
event (for purposes of this guidance, “less common” adverse
reactions). It is difficult to establish that very low frequency
adverse events are caused by a drug, and there will often be large
numbers of these events reported, most of them not caused by the
drug. Lengthy lists of adverse events unlikely to have been caused
by the drug are of little or no value to prescribers, and are
therefore inappropriate for inclusion in labeling.
Serious,
low-frequency adverse events generally will be listed when there is
reason to suspect that the drug may have caused the event. Typical
reasons to suspect causality for an event include (1) timing of
onset or termination with respect to drug use, (2) plausibility in
light of the drug’s known pharmacology, (3) occurrence at a
frequency above that expected in the treated population, and (4)
occurrence of an event typical of drug-induced adverse reactions
(e.g., liver necrosis, agranulocytosis, Stevens-Johnson syndrome).
For serious events that are typical of drug-induced adverse
reactions, the occurrence of even a single event could be a basis
for inclusion in the list. When none of these reasons exist,
however, an event should be excluded from the list. For example, in
a large study of a non-cardiovascular drug in elderly patients, a
certain number of acute myocardial infarctions might be expected
unrelated to the study drug. If the rate in the study does not
exceed the expected rate, those adverse events should be excluded
from the ADVERSE REACTIONS section.
Non-serious,
low-frequency adverse events should be listed only when there is
strong evidence that the drug caused the event. Such evidence may
include, for example, positive challenge/dechallenge tests or rate
of occurrence in a large controlled trial that, although low, is
markedly imbalanced between drug and control arms.
5.
Commentary on Listings of Common and Less Common Adverse Reactions
For adverse reactions with significant
clinical implications (e.g., those that are most commonly occurring,
that result in discontinuation or dose modification, or that require
monitoring), the listings of common and less common adverse
reactions must be supplemented with additional details about the
nature, frequency, severity, dose-response, and demographic
characteristics of the adverse reaction, to the extent data are
available and important (§ 201.57(c)(7)(ii)(A)). It is more likely
that supplemental information will be needed for the more commonly
occurring adverse reactions.
a. Information on Nature, Frequency, and Severity
To the
extent information is available and important and bears on the
nature, frequency, and severity of clinically important adverse
reactions, the commentary must discuss applicable factors (§
201.57(c)(7)(ii)(A)). Examples include:
·
Concomitant therapy
·
Time course of the reaction
·
Steps that can diminish the likelihood or severity of,
or prevent, adverse reactions
·
Changes in adverse reaction rates as a function of
duration of therapy (e.g., increasing or decreasing (tolerance)
rates with increasing duration of therapy, adverse reactions that
emerge only with long-term use)
b. Dose-Response Information
The
commentary must identify clinically significant adverse reactions
that exhibit a dose response (§ 201.57(c)(7)(ii)(A)). It may be
helpful to include a small table showing the dose response for
adverse reactions for which dose response would be expected to
influence dose selection.
c. Demographic and Other Subgroups
The
commentary must include clinically important information about
observed differences, or lack of observed differences, in adverse
reactions in various demographic groups (e.g., age, racial, gender)
(§ 201.57(c)(7)(ii)(A)). If information is available and important,
the commentary should also discuss observed differences, or lack of
observed differences, for other subgroups (e.g., renal failure,
liver failure, different severity levels of same disease). Where
there is no reliable information on differences or similarities in
adverse reaction profiles among demographic subgroups, that fact
should be disclosed, along with an explanation of why such
information is unavailable (e.g., clinical trials were not designed
or powered to detect differences in these populations).
d. Multiple Indications
The commentary should summarize any important differences or
similarities in the adverse reactions profiles for different
indications. If there are substantial and clinically important
differences in adverse reaction profiles between indications, and
the differences cannot be adequately summarized in the commentary,
there should be separate listings of adverse reactions for each
indication. When warranted, clinically important differences or
similarities in adverse reaction profiles for multiple indications
can also be identified in a more prominent location in the ADVERSE
REACTIONS section (e.g., at the beginning of the section).
e. Multiple Formulations
If a
drug has multiple formulations and a certain formulation or
formulations present unique adverse reaction concerns, the
commentary should identify clinically important concerns.
The ADVERSE REACTIONS section must
list adverse reactions identified from domestic and foreign
spontaneous reports (§ 201.57(c)(7)(ii)(B)). This listing must be
separate from the listing of adverse reactions identified in
clinical trials (§ 201.57(c)(7)(ii)(B)) and must also be preceded by
information necessary to interpret the adverse reactions
(§201.57(c)(7)(i)). To help practitioners interpret the significance
of data obtained from postmarketing spontaneous reports, the
following statement, or an appropriate modification, should precede
these data:
The following adverse reactions have been identified during
postapproval use of drug X. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Decisions about whether to include an
adverse event from spontaneous reports in labeling are typically
based on one or more of the following factors: (1) seriousness of
the event, (2) number of reports, or (3) strength of causal
relationship to the drug. When an adverse reaction identified from
spontaneous reporting is included in the labeling, the number of
spontaneous reports ordinarily is not cited, because the number can
quickly become outdated. If the number of reports is cited, the
period of observation should be stated.
The
definition of adverse reactions does not include all adverse events
observed during use of a drug. It is limited to those events for
which there is some basis to believe there is a causal relationship
between occurrence of an adverse event and the use of a drug
(§
201.57(c)(7)). Decisions on whether there is some basis to believe
there is a causal relationship are a matter of judgment and are
based on factors such as: (1) the frequency of reporting, (2)
whether the adverse event rate for the drug exceeds the placebo
rate, (3) the extent of dose-response, (4) the extent to which the
adverse event is consistent with the pharmacology of the drug, (5)
the timing of the event relative to the time of drug exposure, (6)
existence of challenge and dechallenge experience, and (7) whether
the adverse event is known to be caused by related drugs.
For
serious adverse events that are unusual in the absence of drug
therapy (e.g., liver failure, agranulocytosis, rhabdomyolysis,
idiopathic thrombocytopenic purpura, intussusception), there is a
basis to believe there is a causal relationship between the event
and the drug at a very low rate of occurrence. Therefore, these
events are generally listed in the adverse reactions section even if
there are only one or two reported events, unless it is clear that a
causal relationship can be excluded.
The rate of an
identified adverse reaction is ordinarily derived from all reported
adverse events of that type in the database used. Determining a
rate based on a subset of reported events that individual
investigators believe to be causally related to drug exposure is
discouraged. Excluding events from the rate calculation based on
the judgment of individual investigators introduces bias and
inconsistency in rate determinations.
In
characterizing overall adverse reaction experience, nonspecific
terms that lack a commonly understood or precise meaning are
discouraged, as use of such terms can be misleading. For example,
the phrase well-tolerated is a vague and subjective judgment
about a drug’s adverse reaction profile for which there are no
commonly understood parameters. In addition, the terms rare,
infrequent, and frequent do not provide meaningful
information about the frequency of occurrence of adverse reactions.
Specific frequency ranges (e.g., adverse reactions occurring in <
1/500) provide more precise information about incidence.
Comparative safety
claims for drugs in terms of frequency, severity, or character of
adverse reaction must be based on data from adequate and
well-controlled studies (as defined in 21 CFR 314.126), unless this
requirement is waived (§ 201.57(c)(7)(iii)).
Details of studies that are the basis for comparative safety claims
would ordinarily be discussed in the CLINICAL STUDIES section of the
labeling. Care should be taken to avoid inclusion of comparator
rates that would imply a comparative safety claim that is
unsubstantiated or otherwise misleading (e.g., if an excessive dose
of an active comparator was used). If the requirement that claims
be based on adequate and well-controlled studies is waived to permit
inclusion of comparative rates (e.g., because the identity and rates
of adverse reactions for the active comparator are important to
understanding the significance of the information), the comparator
rates should be qualified by a disclaimer indicating that the data
are not an adequate basis for comparison of rates between the study
drug and the active control.
A negative finding can
be reported if the absence of the reaction is convincingly
demonstrated in a trial of adequate design and power.
If there are
no major study-to-study differences in study design, study
population, and adverse reaction rates, an overall pooling of safety
data from multiple studies may increase the precision of adverse
reaction rates and provide a more clinically useful representation
of a drug’s adverse reaction profile.
Adverse
reactions should be classified using meaningful and specific terms
that best communicate the nature and significance of the reaction.
There should ordinarily be a common classification scheme across all
studies in the safety database. Events that are reported under
different terms in the database, but that represent the same
phenomenon (e.g., sedation, somnolence, drowsiness) should
ordinarily be grouped together as a single adverse reaction to avoid
diluting or obscuring the true effect. Similarly, adverse events
reported in more than one body system that appear to represent a
common pathophysiologic event should be grouped together to better
characterize the reaction. For example, an allergic-type adverse
event that has respiratory (wheezing) and dermatologic (rash,
urticaria) manifestations should be classified as a single adverse
reaction (e.g., hypersensitivity).
Within a
listing, adverse reactions must be categorized by body system, by
severity of reaction, in order of decreasing frequency, or by a
combination of these, as appropriate. Within a category, adverse
reactions must be listed in decreasing order of frequency. If
frequency cannot be reliably determined, adverse reactions must be
listed in decreasing order of severity (§ 201.57(c)(7)(ii)).
The frequency
cutoff for the listing of common adverse reactions identified from
clinical trials (usually the adverse reactions table) must be
appropriate to the safety database
(§
201.57(c)(7)(ii)(A)). Factors that could influence selection of a
frequency cut-off include the size of the safety database, the
designs of the trials in the database, and the nature of the
indication. The frequency cutoff should be noted in the listing or
table header, in the text accompanying the listing or table, or in a
footnote.
For
quantitative data (e.g., abnormal laboratory values, vital signs,
ECGs), it is usually preferable to present rates of abnormal values
and to specify the cutoff value for inclusion (e.g., five times the
upper limit of normal) than to refer to a grading system.
The
denominator (N = number of patients) should be provided for each
column in a table or listing, except for the listing of adverse
reactions identified from postmarketing spontaneous reports (see
III.C).
The rates for
reactions that are specific to a subgroup (e.g., gender-specific
reactions such as menstrual irregularity) should be determined using
the appropriate denominator, and that denominator should be
identified in a footnote. If rates of specific adverse reactions
were gathered for only a subgroup of patients or studies (e.g., an
adverse effect on a laboratory test), that fact should be disclosed
in a footnote.
Adverse
reaction rates expressed in percentages should ordinarily be rounded
to the nearest integer. An exception would be for particularly
serious adverse reactions (e.g., stroke, intracranial hemorrhage,
agranulocytosis) occurring at low rates in a large study where
fractions of a percent may be meaningful.
Adverse
reactions for which the placebo rate equals or exceeds the rate for
the drug (after rounding) should not be included in the ADVERSE
REACTIONS section unless there is some compelling factor (e.g.,
timing) that suggests that the event is caused by the drug. In that
case, the adverse reaction should be discussed in the commentary
following the table.
Results of
significance testing should be omitted unless they provide useful
information and are based on a prespecified hypothesis in an
adequately designed and powered study.
Sources
of information to be considered when updating the ADVERSE REACTIONS
section of labeling include controlled trials or epidemiologic
studies conducted after marketing approval, manufacturer's
safety-related labeling supplements, and other analyses of
postmarketing adverse events, including single cases or case series
from the literature or from spontaneous reporting.
Applicants are urged to review at least annually the content of the
ADVERSE REACTIONS section to ensure that the information remains
current. We expect the labeling to be consistent with newly
acquired information from controlled trials or spontaneous reports
and with the evolution of labeling in the pertinent drug class.
Conversely, when there is reliable new adverse reaction information
(either overall information or information relevant to a particular
adverse reaction) that is inconsistent with the information in the
ADVERSE REACTIONS section, we expect the outdated information to be
deleted from all affected sections of the labeling or appropriately
modified, and the new information incorporated in all relevant parts
of the labeling. The applicant must update the labeling when new
information becomes available that causes the labeling to become
inaccurate, false, or misleading (21 CFR 201.56(a)(2)).
Adverse Reaction (21 CFR 201.57(c)(7)):
For purposes of prescription drug labeling and this guidance, an
adverse reaction is an undesirable effect, reasonably associated
with the use of a drug, that may occur as part of the
pharmacological action of the drug or may be unpredictable in its
occurrence. This definition does not include all adverse events
observed during use of a drug, only those for which there is some
basis to believe there is a causal relationship between the drug and
the occurrence of the adverse event.
Adverse reactions may include signs and
symptoms, changes in laboratory parameters, and changes in other
measures of critical body function, such as vital signs and ECG.
Adverse Event (or adverse experience):
For the purposes of this guidance, the term adverse event
refers to any untoward medical event associated with the use of
a drug in humans, whether or not considered drug-related.
Serious Adverse Reaction:
For purposes of this guidance, the term serious adverse reaction
refers to any reaction occurring at any dose that results in any of
the following outcomes: death, a life-threatening adverse
experience, inpatient hospitalization or prolongation of existing
hospitalization, a persistent or significant disability or
incapacity, or a congenital anomaly or birth defect. Important
medical events that may not result in death, be life threatening, or
require hospitalization may be considered serious adverse reactions
when, based upon appropriate medical judgment, they may jeopardize
the patient or subject, and may require medical or surgical
intervention to prevent one of the outcomes listed in this
definition.
This guidance has been prepared
by the Medical Policy Coordinating Committee in the Center for
Drug Evaluation and Research (CDER) in conjunction with the
Center for Biologics Evaluation and Research (CBER).
A table can include less common,
even rare, important events when the database is large enough to
provide a meaningful comparison to a control group.
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Date created: January 18, 2006
