Guidance for Industry
Good Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this
guidance. If you cannot identify the appropriate FDA staff,
call the appropriate number listed on the title page of this
guidance.
I.
INTRODUCTION
This document provides guidance to industry
on good pharmacovigilance practices and pharmacoepidemiologic
assessment of observational data regarding drugs, including
biological drug products (excluding blood and blood components).
Specifically, this document provides guidance on (1) safety signal
identification, (2) pharmacoepidemiologic assessment and safety
signal interpretation, and (3) pharmacovigilance plan
development.
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.
On June 12, 2002, Congress reauthorized, for
the second time, the Prescription Drug User Fee Act (PDUFA III).
In the context of PDUFA III, FDA agreed to satisfy certain
performance goals. One of those goals was to produce guidance for
industry on risk management activities for drug and biological
products. As an initial step towards satisfying that goal, FDA
sought public comment on risk management. Specifically, FDA
issued three concept papers. Each paper focused on one aspect of
risk management, including (1) conducting premarketing risk
assessment, (2) developing and implementing risk minimization
tools, and (3) performing postmarketing pharmacovigilance and
pharmacoepidemiologic assessments. In addition to receiving
numerous written comments regarding the three concept papers, FDA
held a public workshop on April 9 – 11, 2003, to discuss the
concept papers. FDA considered all of the comments received in
developing three draft guidance documents on risk management
activities. The draft guidance documents were published on May 5,
2004, and the public was provided with an opportunity to comment
on them until July 6, 2004. FDA considered all of the comments
received in producing the final guidance documents.
1.
Premarketing Risk Assessment (Premarketing Guidance)
2.
Development and Use of Risk Minimization Action Plans (RiskMAP
Guidance)
3.
Good Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment (Pharmacovigilance Guidance)
Like the concept papers and draft guidances
that preceded them, each of the three final guidance documents
focuses on one aspect of risk management. The Premarketing
Guidance and the Pharmacovigilance Guidance focus on
premarketing and postmarketing risk assessment, respectively. The
RiskMAP Guidance focuses on risk minimization. Together,
risk assessment and risk minimization form what FDA calls risk
management. Specifically, risk management is an iterative
process of (1) assessing a product’s benefit-risk balance, (2)
developing and implementing tools to minimize its risks while
preserving its benefits, (3) evaluating tool effectiveness and
reassessing the benefit-risk balance, and (4) making adjustments,
as appropriate, to the risk minimization tools to further improve
the benefit-risk balance. This four-part process should be
continuous throughout a product’s lifecycle, with the results of
risk assessment informing the sponsor’s decisions regarding risk
minimization.
When reviewing the recommendations provided
in this guidance, sponsors and applicants should keep the
following points in mind:
·
Many recommendations in this guidance are not
intended to be generally applicable to all products.
Industry already
performs risk assessment and risk minimization activities for
products during development and marketing. The Federal Food,
Drug, and Cosmetic Act (FDCA) and FDA implementing regulations
establish requirements for routine risk assessment
and risk minimization (see e.g., FDA requirements for professional
labeling, and adverse event monitoring and reporting). As a
result, many of the recommendations presented here focus on
situations when a product may pose a clinically important and
unusual type or level of risk. To the extent possible, we have
specified in the text whether a recommendation is intended for all
products or only this subset of products.
·
It is of critical importance to protect patients and
their privacy during the generation of safety data and the
development of risk minimization action plans.
During all risk
assessment and risk minimization activities, sponsors must comply
with applicable regulatory requirements involving human subjects
research and patient privacy.
·
To the extent possible, this guidance conforms with
FDA’s commitment to harmonize international definitions and
standards as appropriate.
The topics covered
in this guidance are being discussed in a variety of international
forums. We are participating in these discussions and believe
that, to the extent possible, the recommendations in this guidance
reflect current thinking on related issues.
·
When planning risk assessment and risk minimization
activities, sponsors should consider input from health care
participants likely to be affected by these activities (e.g., from
consumers, pharmacists and pharmacies, physicians, nurses, and
third party payers).
·
There are points of overlap among the three
guidances.
We have
tried to note in the text of each guidance when areas of overlap
occur and when referencing one of the other guidances might be
useful.
Risk assessment during product development
should be conducted in a thorough and rigorous manner; however, it
is impossible to identify all safety concerns during clinical
trials. Once a product is marketed, there is generally a large
increase in the number of patients exposed, including those with
co-morbid conditions and those being treated with concomitant
medical products. Therefore, postmarketing safety data collection
and risk assessment based on observational data are critical for
evaluating and characterizing a product's risk profile and for
making informed decisions on risk minimization.
This guidance document focuses on
pharmacovigilance activities in the post-approval period. This
guidance uses the term pharmacovigilance to mean all
scientific and data gathering activities relating to the
detection, assessment, and understanding of adverse events. This
includes the use of pharmacoepidemiologic studies. These
activities are undertaken with the goal of identifying adverse
events and understanding, to the extent possible, their nature,
frequency, and potential risk factors.
Pharmacovigilance principally involves the
identification and evaluation of safety signals. In this guidance
document, safety signal refers to a concern about an excess
of adverse events compared to what would be expected to be
associated with a product's use. Signals can arise from
postmarketing data and other sources, such as preclinical data and
events associated with other products in the same pharmacologic
class. It is possible that even a single well-documented case
report can be viewed as a signal, particularly if the report
describes a positive rechallenge or if the event is extremely rare
in the absence of drug use. Signals generally indicate the need
for further investigation, which may or may not lead to the
conclusion that the product caused the event. After a signal is
identified, it should be further assessed to determine whether it
represents a potential safety risk and whether other action should
be taken.
Good pharmacovigilance practice is generally
based on acquiring complete data from spontaneous adverse event
reports, also known as case reports. The reports are used to
develop case series for interpretation.
Spontaneous case reports of adverse events
submitted to the sponsor and FDA, and reports from other sources,
such as the medical literature or clinical studies, may generate
signals of adverse effects of drugs. The quality of the reports
is critical for appropriate evaluation of the relationship between
the product and adverse events. FDA recommends that sponsors make
a reasonable attempt to obtain complete information for case
assessment during initial contacts and subsequent follow-up,
especially for serious events,
and encourages sponsors to use trained health care practitioners
to query reporters. Computer-assisted interview technology,
targeted questionnaires, or other methods developed to target
specific events can help focus the line of questioning. When the
report is from a consumer, it is often important to obtain
permission to contact the health care practitioner familiar with
the patient’s adverse event to obtain further medical information
and to retrieve relevant medical records, as needed.
FDA suggests that the intensity and method of
case follow-up be driven by the seriousness of the event reported,
the report's origin (e.g., health care practitioner, patient,
literature), and other factors. FDA recommends that the most
aggressive follow-up efforts be directed towards serious adverse
event reports, especially of adverse events not known to occur
with the drug.
Good case reports include the following
elements:
1.
Description of the adverse events or disease experience, including
time to onset of signs or symptoms;
2. Suspected
and concomitant product therapy details (i.e., dose, lot number,
schedule, dates, duration), including over-the-counter
medications, dietary supplements, and recently discontinued
medications;
3. Patient
characteristics, including demographic information (e.g., age,
race, sex), baseline medical condition prior to product therapy,
co-morbid conditions, use of concomitant medications, relevant
family history of disease, and presence of other risk factors;
4.
Documentation of the diagnosis of the events, including methods
used to make the diagnosis;
5. Clinical
course of the event and patient outcomes (e.g., hospitalization or
death);
6. Relevant
therapeutic measures and laboratory data at baseline, during
therapy, and subsequent to therapy, including blood levels, as
appropriate;
7.
Information about response to dechallenge and rechallenge; and
8. Any other
relevant information (e.g., other details relating to the event or
information on benefits received by the patient, if important to
the assessment of the event).
For reports of medication errors, good case
reports also include full descriptions of the following, when such
information is available:
- Products involved (including the trade
(proprietary) and established (proper) name, manufacturer,
dosage form, strength, concentration, and type and size of
container);
2. Sequence of events leading up to the error;
3. Work environment in which the error occurred; and
4. Types of personnel involved with the error, type(s) of error,
and contributing factors.
FDA recommends that sponsors capture in the
case narrative section of a medication error report all
appropriate information outlined in the National Coordinating
Council for Medication Error Reporting and Prevention (NCC MERP)
Taxonomy.
Although sponsors are not required to use the taxonomy, FDA has
found the taxonomy to be a useful tool to categorize and analyze
reports of medication errors. It provides a standard language and
structure for medication error-related data collected through
reports.
FDA suggests that sponsors initially evaluate
a signal generated from postmarketing spontaneous reports through
a careful review of the cases and a search for additional cases.
Additional cases could be identified from the sponsor’s global
adverse event databases, the published literature, and other
available databases, such as FDA’s Adverse Event Reporting System
(AERS) or Vaccine Adverse Events Reporting System (VAERS), using
thorough database search strategies based on updated coding
terminology (e.g., the Medical Dictionary for Regulatory
Activities (MedDRA)). When available, FDA recommends that
standardized case definitions (i.e., formal criteria for including
or excluding a case) be used to assess potential cases for
inclusion in a case series.
In general, FDA suggests that case-level review occur before other
investigations or analyses. FDA recommends that emphasis usually
be placed on review of serious, unlabeled adverse events, although
other events may warrant further investigation (see section IV.F.
for more details).
As part of the case-level review, FDA
suggests that sponsors evaluate individual case reports for
clinical content and completeness, and follow up with reporters,
as necessary. It is important to remove any duplicate reports.
In assessing case reports, FDA recommends that sponsors look for
features that may suggest a causal relationship between the use of
a product and the adverse event, including:
1. Occurrence
of the adverse event in the expected time (e.g., type 1 allergic
reactions occurring within days of therapy, cancers developing
after years of therapy);
2. Absence of
symptoms related to the event prior to exposure;
3. Evidence
of positive dechallenge or positive rechallenge;
4.
Consistency of the event with the established
pharmacological/toxicological effects of the product, or for
vaccines, consistency with established infectious or immunologic
mechanisms of injury;
5.
Consistency of the event with the known effects of other products
in the class;
6. Existence
of other supporting evidence from preclinical studies, clinical
trials, and/or pharmacoepidemiologic studies; and
7. Absence of
alternative explanations for the event (e.g., no concomitant
medications that could contribute to the event; no co- or
pre-morbid medical conditions).
Confounded cases are common, especially among
patients with complicated medical conditions. Confounded cases
(i.e., cases with adverse events that have possible etiologies
other than the product of concern) could still represent adverse
effects of the product under review. FDA recommends that sponsors
carefully evaluate these cases and not routinely exclude them.
Separate analyses of unconfounded cases may be useful.
For any individual case report, it is rarely
possible to know with a high level of certainty whether the event
was caused by the product. To date, there are no internationally
agreed upon standards or criteria for assessing causality in
individual cases, especially for events that often occur
spontaneously (e.g. stroke, pulmonary embolism). Rigorous
pharmacoepidemiologic studies, such as case-control studies and
cohort studies with appropriate follow-up, are usually employed to
further examine the potential association between a product and an
adverse event.
FDA does not recommend any specific
categorization of causality, but the categories probable,
possible, or unlikely have been used previously.
If a causality assessment is undertaken, FDA suggests that the
causal categories be specified and described in sufficient detail
to understand the underlying logic in the classification.
If the safety signal relates to a medication
error, FDA recommends that sponsors report all known contributing
factors that led to the event. A number of references are
available to assist sponsors in capturing a complete account of
the event.
FDA recommends that sponsors follow up to the extent possible with
reporters to capture a complete account of the event, focusing on
the medication use systems (e.g., prescribing/order
process, dispensing process, administration process). This data
may be informative in developing strategies to minimize future
errors.
In the event that one or more cases suggest a
safety signal warranting additional investigation, FDA recommends
that a case series be assembled and descriptive clinical
information be summarized to characterize the potential safety
risk and, if possible, to identify risk factors. A case
series commonly includes an analysis of the following:
1. The
clinical and laboratory manifestations and course of the event;
2.
Demographic characteristics of patients with events (e.g., age,
gender, race);
3. Exposure
duration;
4. Time from
initiation of product exposure to the adverse event;
5. Doses used
in cases, including labeled doses, greater than labeled doses, and
overdoses;
6. Use of
concomitant medications;
7. The
presence of co-morbid conditions, particularly those known to
cause the adverse event, such as underlying hepatic or renal
impairment;
8. The route
of administration (e.g., oral vs. parenteral);
9. Lot
numbers, if available, for products used in patients with events;
and
10. Changes in
event reporting rate over calendar time or product life cycle.
At various stages of risk identification and
assessment, systematic examination of the reported adverse events
by using statistical or mathematical tools, or so-called data
mining, can provide additional information about the existence
of an excess of adverse events reported for a product. By
applying data mining techniques to large adverse event databases,
such as FDA’s AERS or VAERS, it may be possible to identify
unusual or unexpected product-event combinations warranting
further investigation. Data mining can be used to augment
existing signal detection strategies and is especially useful for
assessing patterns, time trends, and events associated with
drug-drug interactions. Data mining is not a tool for
establishing causal attributions between products and adverse
events.
The methods of data mining currently in use
usually generate a score comparing (1) the fraction of all reports
for a particular event (e.g., liver failure) for a specific drug
(i.e., the “observed reporting fraction”) with (2) the fraction of
reports for the same particular event for all drugs (i.e.,“the
expected reporting fraction”).
This analysis can be refined by adjusting for aspects of reporting
(e.g., the reporting year) or characteristics of the patient
(e.g., age or gender) that might influence the amount of
reporting. In addition, it may be possible to limit data mining
to an analysis for drugs of a specific class or for drugs that are
used to treat a particular disease.
The score (or statistic) generated by data
mining quantifies the disproportionality between the observed and
expected values for a given product-event combination. This score
is compared to a threshold that is chosen by the analyst. A
potential excess of adverse events is operationally defined as any
product-event combination with a score exceeding the specified
threshold. When applying data mining to large databases (such as
AERS), it is not unusual for a product to have several
product-event combinations with scores above a specified
threshold. The lower the threshold, the greater the likelihood
that more combinations will exceed the threshold and will warrant
further investigation.
Several data
mining methods have been described and may be worth considering,
such as the Multi-Item
Gamma Poisson Shrinker (MGPS)
algorithm,,
the Proportional Reporting Ratio (PRR) method,and
the Neural Network approach.
Except when the observed number of cases with the drug event
combination is small (e.g., less than 20) or the expected number
of cases with the drug event combination is < 1, the MGPS and PRR
methods will generally identify similar drug event combinations
for further investigation.
Although all
of these approaches are inherently exploratory or hypothesis
generating, they may provide insights into the patterns of adverse
events reported for a given product relative to other products in
the same class or to all other products. FDA exercises caution
when making such comparisons, because voluntary adverse event
reporting systems such as AERS or VAERS are subject to a variety
of reporting biases (e.g., some observations could reflect
concomitant treatment, not the product itself, and other factors,
including the disease being treated, other co-morbidities or
unrecorded confounders, may cause the events to be reported). In
addition, AERS or VAERS data may be affected by the submission of
incomplete or duplicate reports, under-reporting, or reporting
stimulated by publicity or litigation. As reporting biases may
differ by product and change over time, and could change
differently for different events, it is not possible to predict
their impact on data mining scores.
Use of data
mining techniques is not a required part of signal identification
or evaluation. If data mining results are submitted to FDA, they
should be presented in the larger appropriate clinical
epidemiological context. This should include (1) a description of
the database used, (2) a description of the data mining tool used
(e.g., statistical algorithm, and the drugs, events and
stratifications selected for the analyses) or an appropriate
reference, and (3) a careful assessment of individual case reports
and any other relevant safety information related to the
particular drug-event combination of interest (e.g., results from
preclinical, clinical, pharmacoepidemiologic, or other available
studies).
FDA believes that the methods described above
will permit a sponsor to identify and preliminarily characterize a
safety signal. The actual risk to patients cannot be known from
these data because it is not possible to characterize all events
definitively and because there is invariably under-reporting of
some extent and incomplete information about duration of therapy,
numbers treated, etc. Safety signals that may warrant further
investigation may include, but are not limited to, the following:
1.
New unlabeled adverse events, especially if serious;
2.
An apparent increase in the severity of a labeled event;
3.
Occurrence of serious events thought to be extremely rare in the
general population;
4.
New product-product, product-device, product-food, or
product-dietary supplement interactions;
5.
Identification of a previously unrecognized at-risk population
(e.g., populations with specific racial or genetic predispositions
or co-morbidities);
6.
Confusion about a product's name, labeling, packaging, or use;
7.
Concerns arising from the way a product is used (e.g., adverse
events seen at higher than labeled doses or in populations not
recommended for treatment);
8.
Concerns arising from potential inadequacies of a currently
implemented risk minimization action plan (e.g., reports of
serious adverse events that appear to reflect failure of a RiskMAP
goal);
and
9.
Other concerns identified by the sponsor or FDA.
If a sponsor determines that a concern about an excess of adverse
events or safety signal warrants further investigation and
analysis, it is important to put the signal into context. For
this reason, calculations of the rate at which new cases of
adverse events occur in the product-exposed population (i.e., the
incidence rate) are the hallmark of pharmacoepidemiologic risk
assessment. In pharmacoepidemiologic studies (see section V.A),
the numerator (number of new cases) and denominator (number of
exposed patients and time of exposure or, if known, time at risk)
may be readily ascertainable. In contrast, for spontaneously
reported events, it is not possible to identify all cases because
of under-reporting, and the size of the population at risk is at
best an estimate. Limitations in national denominator estimates
arise because:
1.
Accurate national estimates of the number of patients exposed to a
medical product and their duration of exposure may not be
available;
2. It
may be difficult to exclude patients who are not at risk for an
event, for example, because their exposure is too brief or their
dose is too low;
and
3. A
product may be used in different populations for different
indications, but use estimates are not available for the specific
population of interest.
Although we recognize these limitations, we
recommend that sponsors calculate crude adverse event reporting
rates as a valuable step in the investigation and assessment of
adverse events. FDA suggests that sponsors calculate reporting
rates by using the total number of spontaneously reported cases in
the United States in the numerator and estimates of national
patient exposure to product in the denominator.,
FDA recommends that whenever possible, the number of patients or
person time exposed to the product nationwide be the estimated
denominator for a reporting rate. FDA suggests that other
surrogates for exposure, such as numbers of prescriptions or
kilograms of product sold, only be used when patient-level
estimates are unavailable. FDA recommends that sponsors submit a
detailed explanation of the rationale for selection of a
denominator and a method of estimation.
Comparisons of reporting rates and their
temporal trends can be valuable, particularly across similar
products or across different product classes prescribed for the
same indication. However, such comparisons are subject to
substantial limitations in interpretation because of the inherent
uncertainties in the numerator and denominator used. As a result,
FDA suggests that a comparison of two or more reporting rates be
viewed with extreme caution and generally considered exploratory
or hypothesis-generating. Reporting rates can by no means be
considered incidence rates, for either absolute or comparative
purposes.
To provide further context for incidence
rates or reporting rates, it is helpful to have an estimate of the
background rate of occurrence for the event being evaluated in the
general population or, ideally, in a subpopulation with
characteristics similar to that of the exposed population (e.g.,
premenopausal women, diabetics). These background rates can be
derived from: (1) national health statistics, (2) published
medical literature, or (3) ad hoc studies, particularly of
subpopulations, using large automated databases or ongoing
epidemiologic investigations with primary data collection. FDA
suggests that comparisons of incidence rates or reporting rates to
background rate estimates take into account potential differences
in the data sources, diagnostic criteria, and duration of time at
risk.
While the extent of under-reporting is
unknown, it is usually assumed to be substantial and may vary
according to the type of product, seriousness of the event,
population using the product, and other factors. As a result, a
reporting rate higher than the background rate may, in some cases,
be a strong indicator that the true incidence rate is sufficiently
high to be of concern. However, many other factors affect the
reporting of product-related adverse events (e.g., publicity,
newness of product to the market) and these factors should be
considered when interpreting a high reporting rate. Also, because
of under-reporting, the fact that a reporting rate is less than
the background rate does not necessarily show that the product is
not associated with an increased risk of an adverse event.
FDA recognizes that there are a variety of
methods for investigating a safety signal. Signals warranting
additional investigation can be further evaluated through
carefully designed non-randomized observational studies of the
product’s use in the “real world” and randomized trials. The
Premarketing Guidance discusses a number of types of
randomized trials, including the large simple safety study, which
is a risk assessment method that could be used either pre- or
post-approval.
This document focuses on three types of
non-randomized observational studies: (1) pharmacoepidemiologic
studies, (2) registries, and (3) surveys. By focusing this
guidance on certain risk assessment methods, we do not intend to
advocate the use of these approaches over others. FDA encourages
sponsors to consider all methods to evaluate a particular safety
signal. FDA recommends that sponsors choose the method best
suited to the particular signal and research question of
interest. Sponsors planning to evaluate a safety signal are
encouraged to communicate with FDA as their plans progress.
Pharmacoepidemiologic studies can be of
various designs, including cohort (prospective or retrospective),
case-control, nested case-control, case-crossover, or other
models.
The results of such studies may be used to characterize one or
more safety signals associated with a product, or may examine the
natural history of a disease or drug utilization patterns. Unlike
a case series, a pharmacoepidemiologic study which is designed to
assess the risk attributed to a drug exposure has a protocol and
control group and tests prespecified hypotheses.
Pharmacoepidemiologic studies can allow for the estimation of the
relative risk of an outcome associated with a product, and some
(e.g., cohort studies) can also provide estimates of risk
(incidence rate) for an adverse event. Sponsors can initiate
pharmacoepidemiologic studies at any time. They are sometimes
started at the time of initial marketing, based on questions that
remain after review of the premarketing data. More often,
however, they are initiated when a safety signal has been
identified after approval. Finally, there may also be occasions
when a pharmacoepidemiologic study is initiated prior to marketing
(e.g., to study the natural history of disease or patterns of
product use, or to estimate background rates for adverse events).
For uncommon or delayed adverse events,
pharmacoepidemiologic studies may be the only practical choice for
evaluation, even though they can be limited by low statistical
power. Clinical trials are impractical in almost all cases when
the event rates of concern are less common than 1:2000-3000 (an
exception may be larger trials conducted for some vaccines, which
could move the threshold to 1:10,000). It may also be difficult
to use clinical trials: (1) to evaluate a safety signal associated
with chronic exposure to a product, exposure in populations with
co-morbid conditions, or taking multiple concomitant medications,
or (2) to identify certain risk factors for a particular adverse
event. On the other hand, for evaluation of more common events,
which are seen relatively often in untreated patients, clinical
trials may be preferable to observational studies.
Because pharmacoepidemiologic studies are
observational in nature, they may be subject to confounding,
effect modification, and other bias, which may make results of
these types of studies more difficult to interpret than the
results of clinical trials. Some of these problems can be
surmounted when the relative risk to exposed patients is high.
Because different products pose different
benefit-risk considerations (e.g., seriousness of the disease
being treated, nature and frequency of the safety signal under
evaluation), it is impossible to delineate a universal set of
criteria for the point at which a pharmacoepidemiologic study
should be initiated, and the decision should be made on a
case-by-case basis. When an important adverse event–product
association leads to questions on the product’s benefit-risk
balance, FDA recommends that sponsors consider whether the
particular signal should be addressed with one or more
pharmacoepidemiologic studies. If a sponsor determines that a
pharmacoepidemiologic study is the best method for evaluating a
particular signal, the design and size of the proposed study would
depend on the objectives of the study and the expected frequency
of the events of interest.
When performing a pharmacoepidemiologic
study, FDA suggests that investigators seek to minimize bias and
to account for possible confounding. Confounding by indication is
one example of an important concern in performing a
pharmacoepidemiologic study.
Because of the effects of bias, confounding, or effect
modification, pharmacoepidemiologic studies evaluating the same
hypothesis may provide different or even conflicting results. It
is almost always prudent to conduct more than one study, in more
than one environment and even use different designs. Agreement of
the results from more than one study helps to provide reassurance
that the observed results are robust.
There are a number of references describing
methodologies for pharmacoepidemiologic studies, discussing their
strengths and limitations,
and providing guidelines to facilitate the conduct,
interpretation, and documentation of such studies.
Consequently, this guidance document does not comprehensively
address these topics. However, a protocol for a
pharmacoepidemiologic study generally includes:
1.
Clearly specified study objectives;
2.
A critical review of the literature; and
3.
A detailed description of the research methods, including:
·
the population to be studied;
·
the case definitions to be used;
·
the data sources to be used (including a rationale
for data sources if from outside the U.S.);
·
the projected study size and statistical power
calculations; and
·
the methods for data collection, management, and
analysis.
Depending on the type of
pharmacoepidemiologic study planned, there are a variety of data
sources that may be used, ranging from the prospective collection
of data to the use of existing data, such as data from previously
conducted clinical trials or large databases. In recent years, a
number of pharmacoepidemiologic studies have been conducted in
automated claims databases (e.g., HMO, Medicaid) that allow
retrieval of records on product exposure and patient outcomes. In
addition, recently, comprehensive electronic medical record
databases have also been used for studying drug safety issues.
Depending on study objectives, factors that may affect the choice
of databases include the following:
1.
Demographic characteristics of patients enrolled in the health
plans (e.g., age, geographic location);
2.
Turnover rate of patients in the health plans;
3.
Plan coverage of the medications of interest;
4.
Size and characteristics of the exposed population available for
study;
5.
Availability of the outcomes of interest;
6.
Ability to identify conditions of interest using standard medical
coding systems (e.g., International Classification of Diseases
(ICD-9)), procedure codes or prescriptions that could be used as
markers;
7.
Access to medical records; and
8.
Access to patients for data not captured electronically.
For most pharmacoepidemiologic studies, FDA
recommends that sponsors validate diagnostic findings through a
detailed review of at least a sample of medical records. If the
validation of the specific outcome or exposure of interest using
the proposed database has been previously reported, FDA recommends
that the literature supporting the validity of the proposed study
be submitted for review.
FDA encourages sponsors to communicate with
the Agency when pharmacoepidemiologic studies are being
developed.
The term registry as used in
pharmacovigilance and pharmacoepidemiology can have varied
meanings. In this guidance document, a registry is “an organized
system for the collection, storage, retrieval, analysis, and
dissemination of information on individual persons exposed to a
specific medical intervention who have either a particular
disease, a condition (e.g., a risk factor) that predisposes [them]
to the occurrence of a health-related event, or prior exposure to
substances (or circumstances) known or suspected to cause adverse
health effects.”
Whenever possible, a control or comparison group should be
included, (i.e., individuals with a disease or risk factor who are
not treated or are exposed to medical interventions other than the
intervention of interest).
Through the creation of registries, a sponsor
can evaluate safety signals identified from spontaneous case
reports, literature reports, or other sources, and evaluate
factors that affect the risk of adverse outcomes, such as dose,
timing of exposure, or patient characteristics.
Registries can be particularly useful for:
1.
Collecting outcome information not available in large automated
databases; and
2.
Collecting information from multiple sources (e.g., physician
records, hospital summaries, pathology reports, vital statistics),
particularly when patients receive care from multiple providers
over time.
A sponsor can initiate a registry at any
time. It may be appropriate to initiate the registry at or before
initial marketing, when a new indication is approved, or when
there is a need to evaluate safety signals identified from
spontaneous case reports. In deciding whether to
establish a registry, FDA recommends that a sponsor consider the
following factors:
1.
The types of additional risk information desired;
2.
The attainability of that information through other methods; and
3.
The feasibility of establishing the registry.
Sponsors electing to initiate a registry should develop written
protocols that provide: (1) objectives for the registry, (2) a
review of the literature, and (3) a summary of relevant animal and
human data. FDA suggests that protocols also contain detailed
descriptions of: (1) plans for systematic patient recruitment and
follow-up, (2) methods for data collection, management, and
analysis, and (3) conditions under which the registry will be
terminated. A registry-based monitoring system should include
carefully designed data collection forms to ensure data quality,
integrity, and validation of registry findings against a sample of
medical records or through interviews with health care providers.
FDA recommends that the size of the registry and the period during
which data will be collected be consistent with the safety
questions under study and we encourage sponsors to discuss their
registry development plans with FDA.
Patient or health care provider surveys can
gather information to assess, for example:
1.
A safety signal;
2.
Knowledge about labeled adverse events;
3.
Use of a product as labeled, particularly when the indicated use
is for a restricted population or numerous contraindications
exist;
4.
Compliance with the elements of a RiskMAP (e.g., whether or not a
Medication Guide was provided at the time of product dispensing);
and
5.
Confusion in the practicing community over sound-alike or
look-alike trade (or proprietary) names.
Like a registry, a survey can be initiated by
a sponsor at any time. It can be conducted at the time of initial
marketing (i.e., to fulfill a postmarketing commitment) or when
there is a desire to evaluate safety signals identified from
spontaneous case reports.
FDA suggests that sponsors electing to
initiate a survey develop a written protocol that provides
objectives for the survey and a detailed description of the
research methods, including: (1) patient or provider recruitment
and follow-up, (2) projected sample size, and (3) methods for data
collection, management, and analysis.
FDA recommends that a survey-based monitoring system include
carefully designed survey instruments and validation of survey
findings against a sample of medical or pharmacy records or
through interviews with health care providers, whenever possible.
FDA recommends that survey instruments be validated or piloted
before implementation. FDA suggests that sponsors consider
whether survey translation and cultural validation would be
important.
Sponsors are encouraged to discuss their
survey development plans with FDA.
After identifying a safety signal, FDA
recommends that a sponsor conduct a careful case level review and
summarize the resulting case series descriptively. To help
further characterize a safety signal, a sponsor can also: (1)
employ data mining techniques, and (2) calculate reporting rates
for comparison to background rates. Based on these findings and
other available data (e.g., from preclinical or other sources),
FDA suggests that a sponsor consider further study (e.g.,
observational studies) to establish whether or not a potential
safety risk exists.
When evaluation of a safety signal suggests
that it may represent a potential safety risk, FDA recommends that
a sponsor submit a synthesis of all available safety information
and analyses performed, ranging from preclinical findings to
current observations. This submission should include the
following:
1.
Spontaneously reported and published case reports, with
denominator or exposure information to aid interpretation;
2.
Background rate for the event in general and specific patient
populations, if available;
3.
Relative risks, odds ratios, or other measures of association
derived from pharmacoepidemiologic studies;
4.
Biologic effects observed in preclinical studies and
pharmacokinetic or pharmacodynamic effects;
5.
Safety findings from controlled clinical trials; and
6.
General marketing experience with similar products in the class.
After the available safety information is
presented and interpreted, it may be possible to assess the degree
of causality between use of a product and an adverse event. FDA
suggests that the sponsor’s submission provide an assessment of
the benefit-risk balance of the product for the population of
users as a whole and for identified at-risk patient populations,
and, if appropriate, (1) propose steps to further investigate the
signal through additional studies, and (2) propose risk
minimization actions.
FDA will make its own assessment of the potential safety risk
posed by the signal in question, taking into account the
information provided by the sponsor and any additional relevant
information known to FDA (e.g., information on other products in
the same class) and will communicate its conclusions to the
sponsor whenever possible. Factors that are typically considered
include:
1.
Strength of the association (e.g., relative risk of the adverse
event associated with the product);
2.
Temporal relationship of product use and the event;
3.
Consistency of findings across available data sources;
4.
Evidence of a dose-response for the effect;
5.
Biologic plausibility;
6.
Seriousness of the event relative to the disease being treated;
7.
Potential to mitigate the risk in the population;
8.
Feasibility of further study using observational or controlled
clinical study designs; and
9.
Degree of benefit the product provides, including availability of
other therapies.
As noted in section II, risk management is an
iterative process and steps to further investigate a potential
safety risk, assess the product’s benefit-risk balance, and
implement risk minimization tools would best occur in a logical
sequence, not simultaneously. Not all steps may be recommended,
depending on the results of earlier steps.
FDA recommends that assessment of causality and of strategies to
minimize product risk occur on an ongoing basis, taking into
account the findings from newly completed studies.
For most products, routine pharmacovigilance
(i.e., compliance with applicable postmarket requirements under
the FDCA and FDA implementing regulations) is sufficient for
postmarketing risk assessment. However, in certain limited
instances, unusual safety risks may become evident before approval
or after a product is marketed that could suggest that
consideration by the sponsor of a pharmacovigilance plan may be
appropriate. A pharmacovigilance plan is a plan developed by a
sponsor that is focused on detecting new safety risks and/or
evaluating already identified safety risks. Specifically, a
pharmacovigilance plan describes pharmacovigilance efforts above
and beyond routine postmarketing spontaneous reporting, and is
designed to enhance and expedite the sponsor’s acquisition of
safety information.
The development of pharmacovigilance plans may be useful at the
time of product launch or when a safety risk is identified during
product marketing. FDA recommends that a sponsor’s decision to
develop a pharmacovigilance plan be based on scientific and
logistical factors, including the following:
1.
The likelihood that the adverse event represents a potential
safety risk;
2.
The frequency with which the event occurs (e.g., incidence rate,
reporting rate, or other measures available);
3.
The severity of the event;
4.
The nature of the population(s) at risk;
5.
The range of patients for which the product is indicated (broad
range or selected populations only); and
6.
The method by which the product is dispensed (through pharmacies
or performance linked systems only).
A pharmacovigilance plan may be developed by
itself or as part of a Risk Minimization Action Plan (RiskMAP), as
described in the RiskMAP Guidance. Sponsors may meet with
representatives from the appropriate Office of New Drugs review
division and the Office of Drug Safety in CDER, or the appropriate
Product Office and the Division of Epidemiology, Office of
Biostatistics and Epidemiology in CBER regarding the specifics of
a given product’s pharmacovigilance plan.
FDA believes that for a product without
safety risks identified pre- or post-approval and for which
at-risk populations are thought to have been adequately studied,
routine spontaneous reporting will be sufficient for postmarketing
surveillance. On the other hand, pharmacovigilance plans may be
appropriate for products for which: (1) serious safety risks have
been identified pre- or post-approval, or (2) at-risk populations
have not been adequately studied. Sponsors may discuss with the
Agency the nature of the safety concerns posed by such a product
and the determination whether a pharmacovigilance plan is
appropriate.
A pharmacovigilance plan could include one or
more of the following elements:
1.
Submission of specific serious adverse event reports in an
expedited manner beyond routine required reporting (i.e., as
15-day reports);
2.
Submission of adverse event report summaries at more frequent,
prespecified intervals (e.g., quarterly rather than annually);
3.
Active surveillance to identify adverse events that may or may not
be reported through passive surveillance. Active surveillance can
be (1) drug based: identifying adverse events in patients
taking certain products, (2) setting based: identifying
adverse events in certain health care settings where they are
likely to present for treatment (e.g., emergency departments,
etc.), or (3) event based: identifying adverse events that
are likely to be associated with medical products (e.g., acute
liver failure);
4.
Additional pharmacoepidemiologic studies (for example, in
automated claims databases or other databases) using cohort,
case-control, or other appropriate study designs (see section V);
5.
Creation of registries or implementation of patient or health care
provider surveys (see section V); and
6.
Additional controlled clinical trials.
As data emerges, FDA recommends that a sponsor re-evaluate the
safety risk and the effectiveness of its pharmacovigilance plan.
Such re-evaluation may result in revisions to the
pharmacovigilance plan for a product. In some circumstances, FDA
may decide to bring questions on potential safety risks and
pharmacovigilance plans before its Drug Safety and Risk Management
Advisory Committee or the FDA Advisory Committee dealing with the
specific product in question. Such committees may be convened
when FDA seeks: (1) general advice on the design of
pharmacoepidemiologic studies, (2) comment on specific
pharmacoepidemiology studies developed by sponsors or FDA for a
specific product and safety question, or (3) advice on the
interpretation of early signals from a case series and on the need
for further investigation in pharmacoepidemiologic studies.
While additional information is being developed, sponsors
working with FDA can take interim actions to communicate
information about potential safety risks (e.g., through labeling)
to minimize the risk to users of the product.
