Guidance for Industry
E2E Pharmacovigilance
Planning
(PDF
version of this document)
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
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Food and Drug Administration
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Center for Biologics Evaluation and Research (CBER)
April 2005
ICH
Guidance for Industry
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)
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.
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.
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.
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.
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
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 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.
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.
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.
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
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
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.
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).
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.
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.
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.
The safety specification should identify risks
believed to be common to the pharmacological class.
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.
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.
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.
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.
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 pharmacovigilance practices
include the elements outlined in the bulleted list above should be
sufficient.
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).
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.
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.
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
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.
·
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
system. Further, information on the use of a drug, such as abuse,
can be targeted at selected sentinel sites14. 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.
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
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 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, gender,
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.
1.
ICH Guidance E2D;
Post-approval Safety Data Management: Definitions and Standards for
Expedited Reporting, 3.1.1 Spontaneous Reports.
2.
Pinkston V, Swain EJ,
Management of adverse drug reactions and adverse event data through
collection, storage, and retrieval. In Stephens MDB, Talbot JCC, and
Routledge PA, eds. Detection of New Adverse Drug Reactions. 4th
ed. 1998; MacMillan Reference Ltd, London. p 282.
3.
Faich GA, U.S. adverse
drug reaction surveillance 1989 – 1994. Pharmacoepidemiology Drug
Safety 1996; 393-398.
4.
Goldman SA, Limitations
and strengths of spontaneous reports data. Clinical Therapeutics
1998; 20 (Suppl C):C40-C44.
5.
Hartmann K, Doser AK,
Kuhn M, Postmarketing safety information: How useful are spontaneous
reports. Pharmacoepidemiology and Drug Safety 1999; 8:S65-S71.
6.
“Responding to Signals”
Waller PC and Arlett PA, in Pharmacovigilance, Editor Mann RD, John
Wiley and Sons Ltd 2002.
7.
DuMouchel W, Bayesian
data mining in large frequency tables, with an application to the
FDA Spontaneous Reporting system. Am Stat 1999; 53:177-190.
8.
Bate A, Lindquist M,
Edwards IR, A Bayesian neural network method for adverse drug
reaction signal generation. Eur J Clin Pharmacology 1998;
54:315-321.
9.
Van Puijenbroek E,
Egberts ACG, Heerdink ER, Leufkens HGM, Detecting drug-drug
interactions using a database for spontaneous adverse drug
reactions: An example with diuretics and non-steroidal
anti-inflammatory drugs. Eur J Clin Pharmacol 2000; 56:733-738.
10.
Venning GR,
Identification of adverse reactions to new drugs. III: Alerting
processes and early warning systems. BMJ 1983; 286:458-460.
11.
Edwards IR, The
management of adverse drug reactions: From diagnosis to signal.
Thérapie 2001; 56:727-733.
12.
In Strom BL (ed.).
Pharmacoepidemiology, 3rd ed. 2002; John Wiley and
Sons, Ltd, New York, NY.
13.
Mitchell AA, Van
Bennekom CM, Louik C, A pregnancy-prevention program in women of
childbearing age receiving isotretinoin. N Engl J Med (1995 Jul 13);
333(2):101-6.
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.
15.
In Mann RD and Andrews
EB (eds.) Pharmacovigilance 2002, John Wiley and Sons, Ltd,
West Sussex, England.
16.
Coulter DM, The New
Zealand intensive medicines monitoring programme in pro-active
safety surveillance. Pharmacoepidemiology and Drug Safety 2000;
9:273-280.
17.
Mackay FJ,
Post-marketing studies. The work of the Drug Safety Research Unit.
Drug Safety 1998;19: 343-353.
18.
Garcia Rodriguez LA,
Perez Gutthann S, Use of the UK General Practice Research Database
for Pharmacoepidemiology. Br. J Clin Pharmacol 1998; 45:419-425.
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.
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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Date created: March 31, 2005 |