E2E Pharmacovigilance Planning

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
E2E Pharmacovigilance
Planning
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 2005
ICH

Guidance for Industry
E2E Pharmacovigilance
Planning
Additional copies are available from:
Office of Training and Communication
Division of Drug Information, HFD-240
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Food and Drug Administration
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Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Office of Communication, Training and
Manufacturers Assistance, HFM-40
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Food and Drug Administration
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http://www.fda.gov/cber/guidelines.htm.
(Tel) Voice Information System at 800-835-4709 or 301-827-1800
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 2005
ICH

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION (1, 1.1) ................................................................................................... 1
A. 	Background (1.2) ............................................................................................................................ 2
B. 	Scope of the Guidance (1.3) ........................................................................................................... 2
II. 	SAFETY SPECIFICATION (2) ...................................................................................... 3
A. 	Elements of the Specification (2.1) ............................................................................................... 4
1. Nonclinical (2.1.1) ........................................................................................................................... 4
2. Clinical (2.1.2) ................................................................................................................................. 4
B. 	Summary (2.2) ................................................................................................................................ 6
III. 	PHARMACOVIGILANCE PLAN (3) ............................................................................ 6
A. 	Structure of the Pharmacovigilance Plan (3.1) ........................................................................... 7
1. Summary of Ongoing Safety Issues (3.1.1) ...................................................................................... 7
2. Routine Pharmacovigilance Practices (3.1.2) ................................................................................. 7
3. Action Plan for Safety Issues (3.1.3) ................................................................................................ 8
4. Summary of Actions To Be Completed, Including Milestones (3.1.4) ............................................. 8
B. 	Pharmacovigilance Methods (3.2) ................................................................................................ 8
IV. 	REFERENCES (4) .......................................................................................................... 10
ANNEX — PHARMACOVIGILANCE METHODS .............................................................. 11

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Guidance for Industry1
E2E Pharmacovigilance Planning
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 (1, 1.1) 2
This guidance is intended to aid in planning pharmacovigilance activities, especially in
preparation for the early postmarketing period of a new drug (in this guidance, the term drug
denotes chemical entities, biotechnology-derived products, and vaccines). The main focus of
this guidance is on a safety specification and pharmacovigilance plan that might be submitted at
the time of license application. The guidance can be used by sponsors to develop a stand-alone
document for regions that prefer this approach or to provide guidance on incorporation of
elements of the safety specification and pharmacovigilance plan into the Common Technical
Document (CTD).
The guidance describes a method for summarizing the important identified risks of a drug,
important potential risks, and important missing information, including the potentially at-risk
populations and situations where the product is likely to be used that have not been studied
preapproval. It proposes a structure for a pharmacovigilance plan and sets out principles of good
practice for the design and conduct of observational studies. It does not describe other methods
to reduce risks from drugs, such as risk communication. The guidance takes into consideration
ongoing work in the three regions and beyond on these issues.
1 This guidance was developed within the Expert Working Group (Efficacy) of the International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been
endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2004. At Step 4 of the process,
the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United
States .
2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee
at Step 4 of the ICH process, November 2004.

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This guidance does not cover the entire scope of pharmacovigilance. It uses the World Health
Organization (WHO) definition of the term pharmacovigilance as “the science and activities
relating to the detection, assessment, understanding and prevention of adverse effects or any
other drug related problems.” This definition encompasses the use of pharmacoepidemiological
studies.
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.
A. 	Background (1.2)
The decision to approve a drug is based on its having a satisfactory balance of benefits and risks
within the conditions specified in the product labeling. This decision is based on the information
available at the time of approval. The knowledge related to the safety profile of the product can
change over time through expanded use in terms of patient characteristics and the number of
patients exposed. In particular, during the early postmarketing period, the product might be used
in settings different from clinical trials and a much larger population might be exposed in a
relatively short timeframe.
Once a product is marketed, new information will be generated, which can have an impact on the
benefits or risks of the product; evaluation of this information should be a continuing process, in
consultation with regulatory authorities. Detailed evaluation of the information generated
through pharmacovigilance activities is important for all products to ensure their safe use. The
benefit-risk balance can be improved by reducing risks to patients through effective
pharmacovigilance that can enable information feedback to the users of medicines in a timely
manner.
Industry and regulators have identified the need for better and earlier planning of
pharmacovigilance activities before a product is approved or a license is granted. This ICH
guidance has been developed to encourage harmonization and consistency and prevent
duplication of effort and could be of benefit to public health programs throughout the world as
they consider new drugs in their countries.
B. 	Scope of the Guidance (1.3)
The guidance could be most useful for new chemical entities, biotechnology-derived products,
and vaccines, as well as for significant changes in established products (e.g., new dosage form,
new route of administration, or new manufacturing process for a biotechnology-derived product)
and for established products that are to be introduced to new populations or in significant new
indications or where a new major safety concern has arisen.

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The purpose of this guidance is to propose a structure for a pharmacovigilance plan and a safety
specification that summarizes the identified and potential risks of the product to be addressed in
the plan. The guidance is divided into the following sections:
• 	Safety specification
• 	Pharmacovigilance plan
• 	Annex — Pharmacovigilance Methods
It is recommended that company pharmacovigilance experts get involved early in product
development. Planning and dialogue with regulators should also start long before license
application. A safety specification and pharmacovigilance plan can also be developed for
products already on the market (e.g., new indication or major new safety concern). The plan
could be used as the basis for discussion of pharmacovigilance activities with regulators in the
different ICH regions and beyond.
For products with important identified risks, important potential risks or important missing
information, the pharmacovigilance plan should include additional actions designed to address
these concerns. For products for which no special concerns have arisen, routine
pharmacovigilance as described in section III.A.2 (3.1.2) of this guidance should be sufficient for
postapproval safety monitoring, without the need for additional actions (e.g., safety studies).
During the course of implementing the various components of the plan, any important emerging
benefit or risk information should be discussed and used to revise the plan.
The following principles underpin this guidance:
• 	Planning of pharmacovigilance activities throughout the product life-cycle
• 	Science-based approach to risk documentation
• 	Effective collaboration between regulators and industry
• 	Applicability of the pharmacovigilance plan across the three ICH regions
II. 	SAFETY SPECIFICATION (2)
The safety specification should be a summary of the important identified risks of a drug,
important potential risks, and important missing information. It should also address the
populations potentially at-risk (where the product is likely to be used), and outstanding safety
questions that warrant further investigation to refine understanding of the benefit-risk profile
during the postapproval period. This safety specification is intended to help industry and
regulators identify any need for specific data collection and also to facilitate the construction of
the pharmacovigilance plan. 	The safety specification can be built initially during the
premarketing phase and, at the time approval is sought, it should reflect the status of issues that
were being followed during development.
The Common Technical Document (CTD), especially the Overview of Safety (2.5.5), Benefits
and Risks Conclusions (2.5.6), and the Summary of Clinical Safety (2.7.4) sections, includes
information relating to the safety of the product and should be the basis of the safety issues
identified in the safety specification. Sponsors should support the safety specification with

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references to specific pages of the CTD or other relevant documents. The safety specification
can be a stand-alone document, usually in conjunction with the pharmacovigilance plan, but
elements can also be incorporated into the CTD. The length of the document will generally
depend on the product and its development program. Appendices can be added if it is considered
important to provide a more detailed explanation of important risks or analyses.
A. 	Elements of the Safety Specification (2.1)
It is recommended that sponsors follow the structure of elements provided below when
compiling the safety specification. The elements of the safety specification that are included are
only a guide. The safety specification can include additional elements, depending on the nature
of the product and its development program. Conversely, for products already on the market with
emerging new safety concerns, only a subset of the elements might be relevant.
The focus of the safety specification should be on the identified risks, important potential risks,
and important missing information. The following elements should be considered for inclusion.
1. 	Nonclinical (2.1.1)
Within the Specification, this section should present nonclinical safety findings that have not
been adequately addressed by clinical data, for example:
• 	Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity,
nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity, etc.)
• 	General pharmacology (cardiovascular, including QT interval prolongation; nervous
system; etc.)
• 	Drug interactions
• 	Other toxicity-related information or data
If the product is intended for use in special populations, consideration should be given to whether
specific nonclinical data needs exist.
2. 	Clinical (2.1.2)
a. 	Limitations of the human safety database
Limitations of the safety database (e.g., related to the size of the study population, study
inclusion/exclusion criteria) should be considered, and the implications of such limitations with
respect to predicting the safety of the product in the marketplace should be explicitly discussed.
Particular reference should be made to populations likely to be exposed during the intended or
expected use of the product in medical practice.
The worldwide experience should be briefly discussed, including:
• 	The extent of the worldwide exposure
• 	Any new or different safety issues identified
• 	Any regulatory actions related to safety

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b. 	Populations not studied in the preapproval phase
The specification should discuss which populations have not been studied or have only been
studied to a limited degree in the preapproval phase. The implications of this with respect to
predicting the safety of the product in the marketplace should be explicitly discussed (CTD
2.5.5). Populations to be considered should include (but might not be limited to):
• 	Children
• 	The elderly
• 	Pregnant or lactating women
• 	Patients with relevant co-morbidity such as hepatic or renal disorders
• 	Patients with disease severity different from that studied in clinical trials
• 	Sub-populations carrying known and relevant genetic polymorphism
• 	Patients of different racial and/or ethnic origins
c. 	Adverse events (AEs)/adverse drug reactions (ADRs)
This section should list the important identified and potential risks that require further
characterization or evaluation. Specific references should be made to guide a reviewer to where
clinical safety data are presented (e.g., relevant sections of the CTD 2.5.5 and 2.7.4).
Discussion of risk factors and potential mechanisms that apply to identified AEs/ADRs should
draw on information from any part of the CTD (nonclinical and clinical) and other relevant
information, such as other drug labels, scientific literature, and postmarketing experience.
Identified risks for further evaluation
More detailed information should be included on the most important identified AEs/ADRs,
which would include those that are serious or frequent and that also might have an impact on the
balance of benefits and risks of the product. This information should include evidence bearing on
a causal relationship, severity, seriousness, frequency, reversibility and at-risk groups, if
available. Risk factors and potential mechanisms should be discussed. These AEs/ADRs should
usually call for further evaluation as part of the pharmacovigilance plan (e.g., frequency in
normal conditions of use, severity, outcome, at-risk groups).
Potential risks for further evaluation
Important potential risks should be described in this section. The evidence that led to the
conclusion that there was a potential risk should be presented. It is anticipated that for any
important potential risk, there should be further evaluation to characterize the association.
d. 	Identified and potential interactions, including food-drug and drug-drug
interactions
Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed.
For each, the evidence supporting the interaction and possible mechanism should be
summarized, and the potential health risks posed for the different indications and in the different
populations should be discussed.

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e. 	Epidemiology
The epidemiology of the indication(s) should be discussed. This discussion should include
incidence, prevalence, mortality and relevant co-morbidity, and should take into account
whenever possible stratification by age, sex, and racial and/or ethnic origin. 	Differences in the
epidemiology in the different regions should be discussed (because the epidemiology of the
indication(s) may vary across regions), if this information is available.
In addition, for important adverse events that may require further investigation, it is useful to
review the incidence rates of these events among patients in whom the drug is indicated (i.e., the
background incidence rates). For example, if condition X is an important adverse event in
patients who are treated with drug Y for disease Z, then it is useful to review the incidence of
condition X in patients with disease Z who are not treated with drug Y; this is the background
rate of condition X among patients with disease Z. Information on risk factors for an adverse
event (condition X) would also be useful to include, if available.
f. 	Pharmacological class effects
The safety specification should identify risks believed to be common to the pharmacological
class.
B. 	Summary (2.2)
At the end of the safety specification, a summary should be provided of the:
• 	Important identified risks
• 	Important potential risks
• 	Important missing information
Sponsors are encouraged to summarize specific ongoing safety issues on an issue-by-issue basis,
including both nonclinical and clinical data that are pertinent to the problem.
III. 	PHARMACOVIGILANCE PLAN (3)
This section gives guidance on the structure of a pharmacovigilance plan. The
pharmacovigilance plan should be based on the safety specification. The specification and plan
can be written as two parts of the same document. The plan would normally be developed by the
sponsor and can be discussed with regulators during product development, prior to approval (i.e.,
when the marketing application is submitted) of a new product, or when a safety concern arises
postmarketing. 	It can be a stand-alone document, but elements could also be incorporated into
the CTD.
For products for which no special concerns have arisen, routine pharmacovigilance as described
in section III.A.2 (3.1.2) of this guidance should be sufficient for postapproval safety monitoring,
without the need for additional actions (e.g., safety studies). However, for products with

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important identified risks, important potential risks, or important missing information, additional
actions designed to address these concerns should be considered.
The length of the document will likely depend on the product and its development program. The
pharmacovigilance plan should be updated as important information on safety becomes available
and milestones are reached.
A. 	Structure of the Pharmacovigilance Plan (3.1)
Outlined below is a suggested structure for the pharmacovigilance plan. The structure can be
varied depending on the product in question and the issues identified in the safety specification.
1. 	Summary of Ongoing Safety Issues (3.1.1)
At the beginning of the pharmacovigilance plan, a summary should be provided of the:
• 	Important identified risks
• 	Important potential risks
• 	Important missing information
This is important if the pharmacovigilance plan is a separate document from the safety
specification.
2. 	Routine Pharmacovigilance Practices (3.1.2)
Routine pharmacovigilance should be conducted for all medicinal products, regardless of
whether or not additional actions are appropriate as part of a pharmacovigilance plan. This
routine pharmacovigilance should include the following:
• 	Systems and processes that ensure that information about all suspected adverse
reactions that are reported to the personnel of the company are collected and collated in
an accessible manner
• 	The preparation of reports for regulatory authorities:
— Expedited adverse drug reaction (ADR) reports
— Periodic safety update reports (PSURs)
• 	Continuous monitoring of the safety profile of approved products including signal
detection, issue evaluation, updating of labeling, and liaison with regulatory authorities
• 	Other requirements, as defined by local regulations
In some ICH regions, there might be a regulatory requirement to present within the
pharmacovigilance plan an overview of the company’s organization and practices for conducting
pharmacovigilance. In the absence of such a requirement, a statement that the company’s routine

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pharmacovigilance practices include the elements outlined in the bulleted list above should be
sufficient.
3. 	Action Plan for Safety Issues (3.1.3)
The plan for each important safety issue should be presented and justified according to the
following structure:
• 	Safety issue
• 	Objective of proposed action(s)
• 	Action(s) proposed
• 	Rationale for proposed action(s)
• 	Monitoring by the sponsor for safety issue and proposed action(s)
• 	Milestones for evaluation and reporting
Any protocols for specific studies can be provided in the CTD section 5.3.5.4 Other Clinical
Study Reports or other sections as appropriate (e.g., Module 4 if the study is a nonclinical study).
4. 	Summary of Actions To Be Completed, Including Milestones (3.1.4)
An overall pharmacovigilance plan for the product bringing together the actions for all individual
safety issues should be presented. Whereas section 3.1.3 suggests presenting an action plan by
ongoing safety issue, for this section the pharmacovigilance plan for the product should be
organized in terms of the actions to be undertaken and their milestones. The reason for this is
that one proposed action (e.g., a prospective safety cohort study) could address more than one of
the identified issues.
It is recommended that milestones for completion of studies and other evaluations, and for
submission of safety results, be included in the pharmacovigilance plan. In developing these
milestones, one should consider when:
• 	Exposure to the product will have reached a level sufficient to allow potential
identification/characterization of the AEs/ADRs of concern or resolution of a particular
concern, and/or
• 	The results of ongoing or proposed safety studies are expected to be available.
These milestones might be aligned with regulatory milestones (e.g., PSURs, annual reassessment
and license renewals) and used to revise the pharmacovigilance plan.
B. 	Pharmacovigilance Methods (3.2)
The best method to address a specific situation can vary, depending on the product, the
indication, the population being treated and the issue to be addressed. The method chosen can
also depend on whether an identified risk, potential risk, or missing information is the issue and
whether signal detection, evaluation, or safety demonstration is the main objective of further
study. When choosing a method to address a safety concern, sponsors should employ the most

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appropriate design. The Annex provides a summary of the key methods used in
pharmacovigilance. This is provided to aid sponsors considering possible methods to address
specific issues identified by the safety specification. This list is not all-inclusive, and sponsors
should use the most up-to-date methods that are relevant and applicable.
Design and Conduct of Observational Studies (3.2.1)
Carefully designed and conducted pharmacoepidemiological studies, specifically observational
(noninterventional, nonexperimental) studies, are important tools in pharmacovigilance. In
observational studies, the investigator “observes and evaluates results of ongoing medical care
without 'controlling' the therapy beyond normal medical practice.” 1
Before the observational study that is part of a pharmacovigilance plan commences, a protocol
should be finalized. Experts from relevant disciplines (e.g., pharmacovigilance experts,
pharmacoepidemiologists and biostatisticians) should be consulted. 	It is recommended that the
protocol be discussed with the regulatory authorities before the study starts. It is also suggested
that the circumstances in which a study should be terminated early be discussed with regulatory
authorities and documented in advance. A study report after completion, and interim reports if
appropriate, should be submitted to the authorities according to the milestones within the
pharmacovigilance plan.
Study protocols should, as a minimum, include the study aims and objectives, the methods to be
used, and the plan for analysis. The final study report should accurately and completely present
the study objectives, methods, results, and the principal investigator’s interpretation of the
findings.
It is recommended that the sponsor follow good epidemiological practice for observational
studies and also internationally accepted guidelines, such as the guidelines endorsed by the
International Society for Pharmacoepidemiology.2 In some of the ICH regions, local laws and
guidelines also apply to the design and conduct of observational studies and should be followed.
The highest possible standards of professional conduct and confidentiality should always be
maintained, and any relevant national legislation on data protection followed.

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IV. 	REFERENCES (4)
1. 	CIOMS, Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of
CIOMS Working Group V. Geneva; World Health Organization (WHO), 2001.
2. 	Guidelines for Good Pharmacoepidemiology Practices (GPP), International Society for
Pharmacoepidemiology, http://www.pharmacoepi.org/resources/guidelines_08027.cfm,
August 2004.

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ANNEX — PHARMACOVIGILANCE METHODS
1. 	Passive Surveillance
• 	Spontaneous Reports
A spontaneous report is an unsolicited communication by healthcare professionals or consumers
to a company, regulatory authority or other organization (e.g., WHO, regional centers, poison
control center) that describes one or more adverse drug reactions in a patient who was given one
or more medicinal products and that does not derive from a study or any organized data
collection scheme. 1
Spontaneous reports play a major role in the identification of safety signals once a drug is
marketed. In many instances, a company can be alerted to rare adverse events that were not
detected in earlier clinical trials or other premarketing studies. Spontaneous reports can also
provide important information on at-risk groups, risk factors, and clinical features of known
serious adverse drug reactions. Caution should be exercised in evaluating spontaneous reports,
especially when comparing drugs. The data accompanying spontaneous reports are often
incomplete, and the rate at which cases are reported is dependent on many factors including the
time since launch, pharmacovigilance-related regulatory activity, media attention, and the
indication for use of the drug.2, 3, 4, 5
Systematic Methods for the Evaluation of Spontaneous Reports
More recently, systematic methods for the detection of safety signals from spontaneous reports
have been used. Many of these techniques are still in development and their usefulness for
identifying safety signals is being evaluated. These methods include the calculation of the
proportional reporting ratio, as well as the use of Bayesian and other techniques for signal
detection.6, 7, 8 Data mining techniques have also been used to examine drug-drug interactions. 9
Data mining techniques should always be used in conjunction with, and not in place of, analyses
of single case reports. Data mining techniques facilitate the evaluation of spontaneous reports by
using statistical methods to detect potential signals for further evaluation. This tool does not
quantify the magnitude of risk, and caution should be exercised when comparing drugs. Further,
when using data mining techniques, consideration should be given to the threshold established
for detecting signals, since this will have implications for the sensitivity and specificity of the
method (a high threshold is associated with high specificity and low sensitivity). Confounding
factors that influence spontaneous adverse event reporting are not removed by data mining.
Results of data mining should be interpreted with the knowledge of the weaknesses of the
spontaneous reporting system and, more specifically, the large differences in the ADR reporting
rate among different drugs and the many potential biases inherent in spontaneous reporting. All
signals should be evaluated recognizing the possibility of false positives. In addition, the
absence of a signal does not mean that a problem does not exist.

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• 	Case Series
Series of case reports can provide evidence of an association between a drug and an adverse
event, but they are generally more useful for generating hypotheses than for verifying an
association between drug exposure and outcome. There are certain distinct adverse events known
to be associated more frequently with drug therapy, such as anaphylaxis, aplastic anemia, toxic
epidermal necrolysis and Stevens-Johnson Syndrome.10, 11 Therefore, when events such as these
are spontaneously reported, sponsors should place more emphasis on these reports for detailed
and rapid follow-up.
2. 	Stimulated Reporting
Several methods have been used to encourage and facilitate reporting by health professionals in
specific situations (e.g., in-hospital settings) for new products or for limited time periods. 12 Such
methods include on-line reporting of adverse events and systematic stimulation of reporting of
adverse events based on a predesigned method. Although these methods have been shown to
improve reporting, they are not devoid of the limitations of passive surveillance, especially
selective reporting and incomplete information.
During the early postmarketing phase, companies might actively provide health professionals
with safety information, and at the same time encourage cautious use of new products and the
submission of spontaneous reports when an adverse event is identified. A plan can be developed
before the product is launched (e.g., through site visits by company representatives, by direct
mailings or faxes, etc.). Stimulated adverse event reporting in the early postmarketing phase can
lead companies to notify healthcare professionals of new therapies and provide safety
information early in use by the general population (e.g., Early Post-marketing Phase Vigilance,
EPPV in Japan). This should be regarded as a form of spontaneous event reporting; thus, data
obtained from stimulated reporting cannot be used to generate accurate incidence rates, but
reporting rates can be estimated.
3. 	Active Surveillance
Active surveillance, in contrast to passive surveillance, seeks to ascertain completely the number
of adverse events via a continuous preorganized process. An example of active surveillance is
the follow-up of patients treated with a particular drug through a risk management program.
Patients who fill a prescription for this drug may be asked to complete a brief survey form and
give permission for later contact.13 In general, it is more feasible to get comprehensive data on
individual adverse event reports through an active surveillance system than through a passive
reporting system.
• 	Sentinel Sites
Active surveillance can be achieved by reviewing medical records or interviewing patients
and/or physicians in a sample of sentinel sites to ensure complete and accurate data on reported
adverse events from these sites. The selected sites can provide information, such as data from
specific patient subgroups, that would not be available in a passive spontaneous reporting

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system. Further, information on the use of a drug, such as abuse, can be targeted at selected
sentinel sites 14 . Some of the major weaknesses of sentinel sites are problems with selection bias,
small numbers of patients, and increased costs. Active surveillance with sentinel sites is most
efficient for those drugs used mainly in institutional settings such as hospitals, nursing homes,
hemodialysis centers, etc. Institutional settings can have a greater frequency of use for certain
drug products and can provide an infrastructure for dedicated reporting. In addition, automatic
detection of abnormal laboratory values from computerized laboratory reports in certain clinical
settings can provide an efficient active surveillance system. Intensive monitoring of sentinel sites
can also be helpful in identifying risks among patients taking orphan drugs.
• 	Drug Event Monitoring
Drug event monitoring is a method of active pharmacovigilance surveillance. In drug event
monitoring, patients might be identified from electronic prescription data or automated health
insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or
patient at prespecified intervals to obtain outcome information. Information on patient
demographics, indication for treatment, duration of therapy (including start dates), dosage,
clinical events, and reasons for discontinuation can be included in the questionnaire.12, 15, 16, 17
Limitations of drug event monitoring can include poor physician and patient response rates and
the unfocused nature of data collection, which can obscure important signals. In addition,
maintenance of patient confidentiality might be a concern. On the other hand, more detailed
information on adverse events from a large number of physicians and/or patients might be
collected.
• 	Registries
A registry is a list of patients presenting with the same characteristic(s). This characteristic can
be a disease (disease registry) or a specific exposure (drug registry). Both types of registries,
which only differ by the type of patient data of interest, can collect a battery of information using
standardized questionnaires in a prospective fashion. Disease registries, such as registries for
blood dyscrasias, severe cutaneous reactions, or congenital malformations can help collect data
on drug exposure and other factors associated with a clinical condition. A disease registry might
also be used as a base for a case-control study comparing the drug exposure of cases identified
from the registry and controls selected from either patients with another condition within the
registry, or patients outside the registry.
Exposure (drug) registries address populations exposed to drugs of interest (e.g., registry of
rheumatoid arthritis patients exposed to biological therapies) to determine if a drug has a special
impact on this group of patients. Some exposure (drug) registries address drug exposures in
specific populations, such as pregnant women. Patients can be followed over time and included
in a cohort study to collect data on adverse events using standardized questionnaires. Single
cohort studies can measure incidence, but, without a comparison group, cannot provide proof of
association. However, they can be useful for signal amplification, particularly for rare outcomes.
This type of registry can be very valuable when examining the safety of an orphan drug indicated
for a specific condition.

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4. 	Comparative Observational Studies
Traditional epidemiologic methods are a key component in the evaluation of adverse events.
There are a number of observational study designs that are useful in validating signals from
spontaneous reports or case series. Major types of these designs are cross-sectional studies, case-
control studies, and cohort studies (both retrospective and prospective). 12, 15
• 	Cross-sectional Study (Survey)
Data collected on a population of patients at a single point in time (or interval of time) regardless
of exposure or disease status constitute a cross-sectional study. These types of studies are
primarily used to gather data for surveys or for ecological analyses. The major drawback of
cross-sectional studies is that the temporal relationship between exposure and outcome cannot be
directly addressed. These studies are best used to examine the prevalence of a disease at one time
point or to examine trends over time, when data for serial time points can be captured. These
studies can also be used to examine the crude association between exposure and outcome in
ecologic analyses. Cross-sectional studies are best utilized when exposures do not change over
time.
• 	Case-control Study
In a case-control study, cases of disease (or events) are identified. Controls, or patients without
the disease or event of interest, are then selected from the source population that gave rise to the
cases. The controls should be selected in such a way that the prevalence of exposure among the
controls represents the prevalence of exposure in the source population. The exposure status of
the two groups is then compared using the odds ratio, which is an estimate of the relative risk of
disease in the two groups. Patients can be identified from an existing database or using data
collected specifically for the purpose of the study of interest. If safety information is sought for
special populations, the cases and controls can be stratified according to the population of
interest (the elderly, children, pregnant women, etc.). For rare adverse events, existing large
population-based databases are a useful and efficient means of providing needed drug exposure
and medical outcome data in a relatively short period of time. Case-control studies are
particularly useful when the goal is to investigate whether there is an association between a drug
(or drugs) and one specific rare adverse event, as well as to identify risk factors for adverse
events. Risk factors can include conditions such as renal and hepatic dysfunction, that might
modify the relationship between the drug exposure and the adverse event. Under specific
conditions, a case-control study can provide the absolute incidence rate of the event. If all cases
of interest (or a well-defined fraction of cases) in the catchment area are captured and the
fraction of controls from the source population is known, an incidence rate can be calculated.
• 	Cohort Study
In a cohort study, a population-at-risk for the disease (or event) is followed over time for the
occurrence of the disease (or event). Information on exposure status is known throughout the
follow-up period for each patient. A patient might be exposed to a drug at one time during
follow-up, but nonexposed at another time point. Since the population exposure during follow-up

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is known, incidence rates can be calculated. In many cohort studies involving drug exposure,
comparison cohorts of interest are selected on the basis of drug use and followed over time.
Cohort studies are useful when there is a need to know the incidence rates of adverse events in
addition to the relative risks of adverse events. Multiple adverse events can also be investigated
using the same data source in a cohort study. However, it can be difficult to recruit sufficient
numbers of patients who are exposed to a drug of interest (such as an orphan drug) or to study
very rare outcomes. Like case-control studies, the identification of patients for cohort studies
can come from large automated databases or from data collected specifically for the study at
hand. In addition, cohort studies can be used to examine safety issues in special populations (the
elderly, children, patients with co-morbid conditions, pregnant women) through over-sampling
of these patients or by stratifying the cohort if sufficient numbers of patients exist.
There are several automated databases available for pharmacoepidemiologic studies. 12, 15, 18 They
include databases that contain automated medical records or automated accounting/billing
systems. Databases that are created from accounting/billing systems might be linked to pharmacy
claims and medical claims databases. These datasets might include millions of patients. Since
they are created for administrative or billing purposes, they might not have the detailed and
accurate information needed for some research, such as validated diagnostic information or
laboratory data. Although medical records can be used to ascertain and validate test results and
medical diagnoses, one should be cognizant of the privacy and confidentiality regulations that
apply to patient medical records.
5. 	Targeted Clinical Investigations
When significant risks are identified from preapproval clinical trials, further clinical studies
might be called for to evaluate the mechanism of action for the adverse reaction. In some
instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine
whether a particular dosing instruction can put patients at an increased risk of adverse events.
Genetic testing can also provide clues about which group of patients might be at an increased
risk of adverse reactions. Furthermore, based on the pharmacological properties and the expected
use of the drug in general practice, conducting specific studies to investigate potential drug-drug
interactions and food-drug interactions might be called for. These studies can include population
pharmacokinetic studies and drug concentration monitoring in patients and normal volunteers.
Sometimes, potential risks or unforeseen benefits in special populations might be identified from
preapproval clinical trials, but cannot be fully quantified due to small sample sizes or the
exclusion of subpopulations of patients from these clinical studies. These populations might
include the elderly, children, or patients with renal or hepatic disorder. Children, the elderly, and
patients with co-morbid conditions might metabolize drugs differently than patients typically
enrolled in clinical trials. Further clinical trials might be used to determine and to quantify the
magnitude of the risk (or benefit) in such populations.
To elucidate the benefit-risk profile of a drug outside of the formal/traditional clinical trial
setting and/or to fully quantify the risk of a critical but relatively rare adverse event, a large
simplified trial might be conducted. Patients enrolled in a large simplified trial are usually
randomized to avoid selection bias. In this type of trial, though, the event of interest will be

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focused to ensure a convenient and practical study. One limitation of this method is that the
outcome measure might be too simplified and this might have an impact on the quality and
ultimate usefulness of the trial. Large, simplified trials are also resource-intensive.
6. 	Descriptive Studies
Descriptive studies are an important component of pharmacovigilance, although not for the
detection or verification of adverse events associated with drug exposures. These studies are
primarily used to obtain the background rate of outcome events and/or establish the prevalence
of the use of drugs in specified populations.
• 	Natural History of Disease
The science of epidemiology originally focused on the natural history of disease, including the
characteristics of diseased patients and the distribution of disease in selected populations, as well
as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of
interest now include a description of disease treatment patterns and adverse events. Studies that
examine specific aspects of adverse events, such as the background incidence rate of or risk
factors for the adverse event of interest, can be used to assist in putting spontaneous reports into
perspective.15 For example, an epidemiologic study can be conducted using a disease registry to
understand the frequency at which the event of interest might occur in specific subgroups, such
as patients with concomitant illnesses.
• 	Drug Utilization Study
Drug utilization studies (DUS) describe how a drug is marketed, prescribed, and used in a
population, and how these factors influence outcomes, including clinical, social, and economic
outcomes.12 	These studies provide data on specific populations, such as the elderly, children, or
patients with hepatic or renal dysfunction, often stratified by age, sex, concomitant medication,
and other characteristics. DUS can be used to determine if a product is being used in these
populations. From these studies denominator data can be developed for use in determining rates
of adverse drug reactions. DUS have been used to describe the effect of regulatory actions and
media attention on the use of drugs, as well as to develop estimates of the economic burden of
the cost of drugs. DUS can be used to examine the relationship between recommended and actual
clinical practice. These studies can help to determine whether a drug has the potential for drug
abuse by examining whether patients are taking escalating dose regimens or whether there is
evidence of inappropriate repeat prescribing. Important limitations of these studies can include a
lack of clinical outcome data or information of the indication for use of a product.

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Expedited Reporting, 3.1.1 Spontaneous Reports.
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14. Task Force on Risk Management. Report to the FDA Commissioner. Managing the risks
from medical product use: Creating a risk management framework. Part 3. How does FDA
conduct postmarketing surveillance and risk assessment. May 1999.
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