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80 Cobert’s Manual of Drug Safety and Pharmacovigilance
25. Risk Identification and Evaluation
a. Ongoing Safety Evaluation
Sponsors should develop a system to
assess, evaluate, and act on safety infor-
mation on a continuous basis during drug
development to ensure the earliest pos-
sible identification of safety concerns to
allow risk minimization.
The integrity of the studies should not be
compromised by the safety monitoring
and analysis.
b. Safety Data Management
Safety data should be handled using con-
sistent standards and criteria, with care
and precision.
Safety evaluations must be individual-
ized for each product because there are
no standard approaches to evaluating or
measuring “an acceptable level of risk”.
26. Review of Safety Information
a. Safety data analysis should involve both indi-
vidual case reports as well as aggregate data.
Individual cases should be reviewed within
specified time frames and aggregate data
periodically.
b. The evaluation should be done in the con-
text of the patient population, the indication
studied, the natural history of the disease,
and currently available alternative therapies.
c. Causality determinations should be done for
all reported cases. The investigator causal-
ity assessment should be taken into account
when the sponsor is reviewing the safety
information.
d. AEs of special interest (AESI) should be
identified in the protocol and handled as if
they are serious even if they do not meet the
regulatory definition of serious.
e. Non-serious AEs should be reviewed to see
whether there are events of special interest,
with particular attention paid to those asso-
ciated with subject discontinuation from the
study.
27. Frequency of Review of Safety
Information
a. Safety review of all data should be done
frequently:
Ad hoc for serious and special interest AEs;
Routine periodic review of all data whose
frequency varies from trial to trial or pro-
gram to program;
Reviews triggered by specific trial or pro-
gram milestones;
At the time of study completion and
unblinding.
28. Analysis and Evaluation
a. Subgroup analysis, though possibly limited
by small sample size, should be done for
dose, duration, gender, age, concomitant
medications, and concurrent diseases.
b. Data pooling should include studies that are
of similar design. This can include all con-
trolled studies, placebo-controlled studies,
studies with any positive control, studies
with a particular positive control, and partic-
ular indications.
c. If the duration of treatment varies widely
among participants, data on the effect of
treatment duration should be analyzed.
29. Statistical Approaches
a. The techniques for use of statistics for ana-
lyzing safety data are less well developed
than for efficacy.
b. Statistical association (probability values)
alone may or may not be of clinical value.
Examination of both statistical and clini-
cal significance must involve a partnership
between the statistical and clinical experts.
c. It may be necessary to acknowledge when
the data are insufficient to draw conclusions
on safety: “Absence of evidence is not evi-
dence of absence”.
d. There are several large sections of this report
devoted to specific statistical situations and
techniques, and the reader is referred to the
report for further detail.
Council for International Organizations of Medical Sciences (CIOMS) 81
Regulatory Reporting and
Communications of Safety
Information from Clinical
Trials
The working group notes, in bold type, that these rec-
ommendations are only proposals and do not super-
sede current regulations. They represent proposals for
discussion.
The group endorses ICH Guideline E2A and recom-
mends the harmonization of criteria for expedited
reporting, whereby such reporting to authorities
should include only suspected ADRs that are both
serious and unexpected. Only under exceptional
circumstances should other cases (i.e., expected
cases) be submitted as expedited reports. If report-
ing without regard to causality is required, it should
be done on a periodic basis with clearly defined
timelines and format.
The regulators should adopt the phrase “a reason-
able possibility of a causal relationship” and not use
the ICH E2A phrase of “a causal relationship cannot
be ruled out” in regard to suspected ADRs.
Once a drug is marketed, the company CSI (CCSI)
document should be used as the reference safety
document for determining expectedness for regula-
tory reporting of phase IV trials. For new indication
trials, the DCSI document should be used. The two
documents should be aligned as much as possible.
As with spontaneous reports, reportability for case
reports from trials should be determined at the
event level. That is, a case would be expedited if
there is a suspected adverse reaction that is serious
and unexpected.
Suspected ADRs that are serious and unexpected
and, thus, meet criteria for expedited reporting
should, in general, be unblinded (unblind the sin-
gle case, not the entire study). There may be certain
circumstances where this should not occur, how-
ever (e.g., serious AEs that are also efficacy end-
points). Such exceptions should be agreed on by
the regulatory authorities and be clearly described
in the investigator brochure and the protocol.
Unblinded placebo cases should not be reported to
regulatory authorities as expedited cases. Unblinded
(and open-label) comparator drug cases should be
reported to the regulatory authorities or the com-
pany owning the comparator on an expedited basis,
whether or not expected.
Seven-day reports should be limited to cases from
clinical trials and not spontaneous reports. This
should apply both in countries where the drug is
approved and where it is only under clinical study.
The sponsor should develop clear standard operat-
ing procedures for the expedited or prompt report-
ing of other safety issues, with special attention to
when the clock starts for:
Non-clinical safety issues that might have impli-
cations for human subjects.
A higher incidence of a serious AE for the drug
compared with the comparator or the back-
ground rate in the general population.
An increased frequency of a previously recog-
nized serious adverse reaction.
A significant drug interaction in a pharmacoki-
netic study.
AEs that are deemed not to be drug-related but
are considered study-related.
Contrary to established regulations, the working
group recommends that routine expedited cases
reported to investigators and Institutional Review
Boards (IRBs)/ethics committees (as opposed to
reports to regulatory authorities) be eliminated and
replaced with regular updates of the evolving bene-
fit–risk profile highlighting new safety information.
For unapproved products, the reports to inves-
tigators and IRBs should include a line listing of
unblinded clinical trial cases that were expedited to
regulatory agencies during this time period, a copy
of the current DCSI with an explanation of changes,
and a brief summary of the emerging safety profile.
Quarterly updates are the “default” with other fre-
quencies as appropriate.
For approved products, the reports to investigators
and IRBs should be quarterly if the product is in
82 Cobert’s Manual of Drug Safety and Pharmacovigilance
phase III trials. For well-established products, a
less frequent interval would be acceptable. At some
point, only investigators and IRBs would need to be
updated for significant new information. For phase
IV investigators and IRBs, only changes to the CCSI
would be needed.
The reports, whether for approved or unapproved
products, should include in the line listings only
unblinded expedited reports from trials and include
only interval data (i.e., changes since the last
update). A summary of the emerging safety profile
should be included with cumulative data as needed.
MedDRA
®
should be used. The listings should
not include spontaneous reports, which should be
described in narrative form in the update.
Should a significant safety issue be identified (i.e.,
an issue that has a significant impact on the course
of the clinical trial or program or warrants imme-
diate update of the informed consent), the sponsor
should promptly notify the regulatory authorities,
investigators, IRBs, and, if relevant, data safety
monitoring committees.
A safety management team should review all safety
data on a regular basis: quarterly before approval
and coordinated with the PSUR schedule post-ap-
proval. Ad hoc meetings would occur as needed
to address urgent safety issues and signals. They
would review the overall evolving safety profile to
make changes to the DCSI, informed consent, and
protocol as needed.
A single Development Safety Update Report (DSUR)
should be submitted to regulators annually. The for-
mat and content would be defined and would cover
the drug product, not just a single study.
For marketed products with well-established safety
profiles and for which most trials are in phase IV in
the approved indications, the PSUR would replace
the DSUR.
Sponsors should incorporate the DCSI into every
investigator brochure, either as a special section
of the investigator brochure or as an attachment.
The sponsor should clearly identify the events for
which the company believes there is sufficient evi-
dence to suspect a causal drug relationship. These
events would be considered expected (“listed”) for
regulatory reporting criteria.
The investigator brochure and DCSI should be
reviewed and updated at least annually.
If the developer or manufacturer of a product is
not the sponsor of a particular trial but rather sup-
ports an external clinical or non-clinical investiga-
tor-sponsored study, a provision of any agreement
should be the prompt reporting to the company of
all serious suspected ADRs in humans or significant
findings in animals.
As with the CCSI for marketed drugs (see CIOMS
III/VI), the same threshold criteria should be applied
to the DCSI and informed consent in preapproval
drugs.
Informed consent should be renewed with the sub-
jects whenever there is new information that could
affect the subjects’ willingness to participate in the
trial. In certain circumstances, more immediate
communication may be appropriate.
CIOMS VII (2006):
Development Safety Update
Report (DSUR)
This working group created the concept of the DSUR,
which is the pre-marketing equivalent of the Periodic
Safety Update Report for marketed products. Most
agencies have implemented their own guidance docu-
ments on how to adhere and develop the DSUR locally,
therefore it is in one’s best interest to be familiar with
local regulatory guidance surrounding this report.
There should be one DSUR for one chemical entity.
The goal is to include all new, pertinent, clinical, and
non-clinical safety information, that is, the drug’s
safety profile. It will include cumulative and interval
summaries of key safety data and try to evaluate safety
data in the context of subject exposure. It will describe
new safety issues, summarize known and potential
risks, and give an update on the status of the clini-
cal development program. It will note any urgent or
emerging issues and will note changes to clinical trial
protocols, consent forms, and the IB. It is not meant
to be a signal detection tool or a means to document
or discuss individual cases. The DSUR should be pre-
pared in parallel to the PSUR if the drug is already on
the market. The first authorization anywhere in the
world to conduct a clinical trial will be the develop-
mental international birth date, in the same way that
Council for International Organizations of Medical Sciences (CIOMS) 83
the first approval anywhere in the world creates an
international (marketing) birth date. It will be pre-
pared annually by the sponsor and submitted to the
regulatory agencies within 60 days of the data lock
point. An executive summary plus line listings of seri-
ous ADRs are sent to IRBs and ethics committees. The
reference labeling document will be the investigators’
brochure in place at the beginning of the reporting
period. It may contain some proprietary information,
which may need to be redacted if the document is sent
to places other than regulatory agencies.
CIOMS VIII (2010):
Signal Detection (Points to Consider in Application of
Signal Detection in Pharmacovigilance) This working
group has developed and published a consensus docu-
ment on signaling for consideration by sponsors, health
agencies, and others who deal with drug safety. It takes
a life cycle view of signaling. This is a well-written
summary of the principles of signaling. It is not pre-
scriptive in the sense of mandating a “one-size-fits-all”
policy but rather comes forward with conclusions and
recommendations to be tailored to the particular prod-
uct and situation. Chapter 6 provides a more in-depth
discussion regarding the application of Signal Detection
in Pharmacovigilance.
CIOMS/WHO Working
Group on Vaccine
Pharmacovigilance (2012):
Definitions and Applications
of Terms for Vaccine
Pharmacovigilance
The working group, composed of senior scientists from
developed and emerging countries, prepared a consen-
sus report general terms and definitions for vaccine
pharmacovigilance. The report also considers practical
aspects of how to apply these in vaccine safety surveil-
lance. The report proposes several case definitions for
common vaccine-associated AEs. See the chapter in
this Manual for further information on “Vaccinovigi-
lance” which takes many of the principles created by
the CIOMS/WHO Working group & Brighton Group
into consideration and how to operationalize them in
daily practice.
CIOMS IX (2014): Practical
Approaches to Risk
Minimization for Medicinal
Products
This consensus working group report focuses on how to
minimize the wide variety of risks, serious and non-se-
rious, that are encountered with today’s medicines. All
medicines have risks as well as potential benefits and
routine risk minimization measures are adequate to
manage the risks of most drugs. However, some prod-
ucts require non-routine tools to ensure that their ben-
efits outweigh risks. Such risk minimization tools are
used to prevent harms from occurring or mitigating
them when they occur.
The application of these tools are the topics cov-
ered in this thoughtful and practical report. The recom-
mendations are intended for consideration by sponsors/
applicants, drug regulators, the healthcare community,
and other drug safety stakeholders. The report empha-
sizes that, when necessary, these non-routine risk mini-
mization tools should be customized to the product and
situation. Further, the report recommends selecting risk
minimization tools that will be the least burdensome
on the healthcare system, while achieving the intended
goals. Metrics should also be applied periodically to
measure effectiveness of the tool(s) and possible trig-
gers for program modification.
CIOMS X (2016): Evidence
Synthesis and Meta-analysis
Systematic data reviews and meta-analysis have
an increasingly important role for healthcare deci-
sion-makers and many other stakeholders. A well-done
systematic review can inform many aspects of drug
84 Cobert’s Manual of Drug Safety and Pharmacovigilance
development. This report provides important princi-
ples, considerations, rationale, and recommendations
for appropriate systematic reviews and meta-analysis
to understand the overall best evidence in regulatory
decision-making.
Both pre-marketing and post-marketing phases are
considered and conditions for combining evidence and
the limits of summarizing results. This working group
has carefully described application to both efficacy
data and, separately, to combining evidence on adverse
events. The emphasis of this report is on safety aspects
and adverse events. Much of the report describes highly
technical statistical approaches, important tools for sys-
tematic analysis of safety data for drugs, although there
may be broader conceptual application to other medical
products.
CIOMS SMQs (2016):
Development and Rational
Use of Standardized
MedDRA Queries: Retrieving
Adverse Drug Reactions
with MedDRA — Second
Edition Japanese Translation
Available
Biopharmaceutical companies, drug regulatory author-
ities, vendors, and other stakeholders use MedDRA
®
to
code, exchange, and analyze regulatory information for
medical products. MedDRA is used, particularly with
large amounts of drug safety data stored in databases.
Because of the granularity of MedDRA, detailed search
strategies are needed to identify and retrieve individ-
ual case safety reports of interest from these databases.
Standardized MedDRA Queries (SMQs) have been
developed over more than a decade by senior scientists
from many countries in a cooperative effort of CIOMS
and ICH. SMQs focus on clearly defined conditions of
interest to support a consistent approach to developing
a series of individual safety reports to help answer a
safety question. This second edition of the “Red Book”
provides historical perspectives and “how to” develop,
execute, and interpret output from a query using an
SMQ. It is important to have a good understanding of
SMQs and other safety queries, as there is the possibility
to monitor safety risks and use results in benefit–risk
assessments.
MedDRA
®
is a product of the International Confer-
ence for Harmonization (ICH) owned by the International
Federation of Pharmaceutical Manufacturers Associa-
tions as trustee for ICH.
CIOMS (2017): Guide to
Active Vaccine Safety
Surveillance
This working group developed a guide for vaccine sur-
veillance in resource-constrained areas. This project is
particularly important for national public health pro-
grams when safety of a newly introduced vaccine must
be addressed in low and middle-income countries.
This guide contains consensus principles relevant for
Objective #8 of WHO’s Global Vaccine Safety Initiative
regarding public–private information exchange. More
vaccine products are focused on unmet needs and these
products are reaching previously under-served popula-
tions sooner. The guide has practical advice on steps to
consider if gaps in safety data prompt additional safety
surveillance.
CIOMS ICH Terms and
Definitions
This glossary, most recently updated and published in
February 7, 2024, combines the terms and definitions
included in the guidelines of the International Council
for Harmonization of Technical Requirements for Phar-
maceuticals for Human Use (ICH). It was compiled by
CIOMS from the publicly available guidelines found on
Council for International Organizations of Medical Sciences (CIOMS) 85
the ICH website. The guidelines themselves are owned
by the International Council for Harmonisation of Tech-
nical Requirements for Pharmaceuticals for Human Use
(ICH).
While every effort has been made by CIOMS to
ensure the accuracy of this glossary, there may be unin-
tentional errors or omissions. Please refer to the original
ICH guidelines to verify the information provided. As
ICH adopts new guidelines and introduces new terms
on an irregular basis, CIOMS intends to review and
update this document, e.g., quarterly, or as warranted.
CIOMS (2020) Drug Induced
Liver Injury (DILI)
The consensus report of the CIOMS DILI Working
Group aims to provide a critical framework and essen-
tial set of tools to detect, diagnose, and manage DILI
during drug development and in the post-marketing set-
ting. The report is intended for clinical and basic phar-
maceutical industry investigators who capture, analyze,
and communicate liver safety data in drug develop-
ment. It is also intended for regulatory scientists and
expert consultants who comprehensively evaluate new
products and emerging biomarkers for their association
with DILI risk, and for health care professionals who
monitor and manage patients treated with potentially
hepatotoxic drugs in clinical practice.
CIOMS XI Patient
Involvement in the
Development, Regulation
and Safe Use of Medicines
(2022)
This report describes the importance of systematically
involving patients throughout a medicine’s life — from
its early development through the regulatory pro-
cess to ongoing monitoring and safe use in everyday
healthcare. It provides a comprehensive overview of
the current knowledge about the benefits of patient
involvement and existing initiatives, gives many exam-
ples and recommendations, and addresses the remain-
ing challenges and practice gaps. The report prompts
readers to implement its best practice recommenda-
tions according to how well they fit in with their orga-
nizational and national needs.
The report combines the experience and expertise
of the CIOMS Working Group XI on Patient involve-
ment in the development, regulation and safe use of
medicines. It also incorporates views gathered from
an open meeting in Switzerland and a workshop in
Uganda, which both brought together members of the
public, patient organization representatives, regulators,
drug development experts, industry, academia, health
professionals and other related stakeholders. The report
was finalized following public consultation.
CIOMS XII (2023, Draft) —
Benefit-Risk Balance for
Medicinal Products
This working group was launched in September 2019
and includes participants from industry, regulators, aca-
demia and the World Health Organization. The goal is
to update CIOMS IV on Benefit-Risk Balance for Mar-
keted Drugs: Evaluation of Safety Signals, originally pub-
lished in 1998, and potentially to extend the scope to
include pre-approval as well as post-marketing consid-
erations for medicinal products.
Additional Working Groups
Several additional projects ongoing as of late 2023
include:
Working Group XIII on Real-World Data & Evi-
dence in Regulatory Decision-Making;
Working Group XIV on Artificial Intelligence in
Pharmacovigilance;
86 Cobert’s Manual of Drug Safety and Pharmacovigilance
Working Group XV on Pharmacoepidemiology for
Public Health;
Working Group on MedDRA Labelling Groupings;
Working Group on Severe Cutaneous Adverse Reac-
tions (SCARs);
Working Group on Good Govenance Practice for
Research Institutions;
Working group on Recommended Standards of
Education and Training for Health Professionals
Participating in Medicines Development.
CHAPTER
87
7
International Council
for Harmonization of
Technical Requirements
for Pharmaceuticals for
Human Use (ICH)
I
CH is a global consensus organization
composed of industry, regulators, and
others currently operating as an asso-
ciation under Swiss law to develop tech-
nical guidelines for drug development.
ICH guidelines are non-binding until
adopted by regulators at the local level
as guidance or regulation. This chapter
summarizes key ICH activities at a high
level and some of the guidelines issued
by the various working groups related
to drug safety. These guidelines have
been used as the basis for creating cer-
tain safety guidance and regulations in
North America, Europe, Japan, and else-
where. They are worth taking the time
to review online. Keep in mind that not
all consensus guidelines issued by ICH
have been adopted as requirements
at the national level. Further, some
ICH proposals have been modified by
national regulatory authorities prior to
adoption. Check current local regula-
tions for specifics of what is required in
each regulatory jurisdiction.
ICH was started by drug regulators and industry from
Europe, Japan, and the US in 1990 as a voluntary
consensus organization to improve and harmonize
the drug development process. ICH was conceived
as a forum for bringing together regulatory author-
ities, academic experts and pharmaceutical industry
to discuss scientific and technical aspects of drug reg-
istration. The overall mission is to ensure that safe,
effective, and high quality medicines are developed
and then made available in the most resource-efficient
manner. The original name of the organization was
88 Cobert’s Manual of Drug Safety and Pharmacovigilance
the International Conference on Harmonization of
Technical Requirements for Registration of Pharma-
ceuticals for Human Use. The name was changed as
part of a reorganization and expansion in late 2015 to
the International Council for Harmonisation of Tech-
nical Requirements for Pharmaceuticals for Human
Use.
Along with the name change, ICH expanded par-
ticipation beyond the founding regions to include
additional organizations and extend the benefits of
harmonization. This required a series of organizational
changes. These changes included greater international
outreach, a new governance structure, and broader
communication of ICH processes and work products.
The governance structure evolved from a “six pack”
Steering Committee, which was limited to the six
founding parties and a few observers, to an Assembly
and a Management Committee. Further, ICH is now
a legal non-profit entity under Swiss law. Additional
details regarding the current structure and processes
are published on the ICH website (www.ich.org).
ICH has organized drug development topics
into four categories: Efficacy (E), Quality (Q), Safety
(S), and Multidisciplinary (M). ICH topic codes are
assigned according to these categories. Note that “S”
topics deal with non-clinical safety; clinical safety is
covered under “E” topics. Experts from the various par-
ties are appointed to comprise a working group, which
produces technical documents. These documents usu-
ally take the form of guidelines or Q&A. An established
multi-step process, including public consultation, is
used to achieve final consensus.
Since technology and regulatory science are not
static, ICH guidelines are periodically updated to reflect
this. Revisions are indicated by an “R” in the ICH topic
code. In certain instances, Q&A documents are devel-
oped to provide clarification.
The subset of ICH topics directly relevant to phar-
macovigilance are:
E1: The Extent of Population Exposure to Assess
Clinical Safety for Drugs Intended for Long-Term
Treatment of Non-Life Threatening Conditions;
E2A: Clinical Safety Data Management: Definitions
and Standards for Expedited Reporting;
E2B(R3) and E2B(R2): Maintenance of the Clini-
cal Safety Data Management, including the Mainte-
nance of the Electronic Transmission of Individual
Case Safety Reports Message Specification (Note:
ICH has published several documents in an imple-
mentation package for E2B(R3));
E2C(R2): Periodic Benefit-Risk Evaluation Report
(Note: Relevant parts of a separate document,
E2CA, Addendum to E2C, has been incorporated
into the E2C(R2) guideline);
E2C(R2) Q&As: Questions and Answers: Periodic
Benefit-Risk Evaluation Report;
E2D & E2D(R1) EWG: Post-Approval Safety Data
Management: Definitions and Standards for Expe-
dited Reporting;
E2E: Pharmacovigilance Planning;
E2F: Development Safety Update Report;
E19: Optimisation of Safety Data Collection; and
M1: MedDRA
®
Terminology (Medical Dictionary
for Regulatory Activities).
While the subset above is primarily focused on
safety and pharmacovigilance topics, other ICH Effi-
cacy guidelines are relevant and would be important for
any well-rounded safety & pharmacovigilance profes-
sional. These include:
E3: Clinical Study Reports
E6: Good Clinical Practice
E8: General Considerations in Clinical Trials
E9: Statistical considerations in Clinical Trials
E15: Definitions for Pharmacogenetics/
Pharmacogenomics
E19: Safety Data Collection
In addition to the efficacy guidelines, it would be
prudent for those in study to also familiarize themselves
with the other subset of guidelines in quality (such as
Q7 Good Manufacturing Practice, Q8 Pharmaceutical
Development, Q9 Quality Risk Management and Q10
Pharmaceutical Quality Development.
The ICH consensus documents, as well as informa-
tion on ongoing work, can be found on the ICH web
site (www.ich.org) and, if adopted into local regulatory
requirements (with or without modification), on web
sites of concerned regulators.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) 89
E1: The Extent of Population
Exposure to Assess Clinical
Safety for Drugs Intended
for Long-Term Treatment
of Non-Life Threatening
Conditions
This guideline was finalized in 1994. It summarizes
principles for safety evaluation of products intended for
chronic use (or repeated intermittent use) of six months
or longer for treatment of non-life-threatening condi-
tions. The duration of drug exposure and its relationship
to both time and magnitude of occurrence of adverse
events are important considerations in determining the
size of the data base necessary to characterize and quan-
tify the safety profile of such a product. It is recommended
that safety data derived from studies of shorter duration
be analyzed separately from studies of longer duration.
Also, the guideline suggests that events where the rate
of occurrence changes over a longer period of time may
need to be characterized depending on their severity and
importance to the risk-benefit assessment of the drug.
Safety data obtained during clinical development would
not be expected to characterize rare adverse events, for
example, those occurring in less than 1 in 1,000 patients.
E2A: Clinical Safety Data
Management: Definitions
and Standards for Expedited
Reporting
E2A combines many concepts from the Council
for International Organizations of Medical Sciences
(CIOMS) I and CIOMS II reports covering the develop-
ment of standard definitions and terminology for safety
reporting and the appropriate mechanism for handling
expedited (alert) reporting. This document was origi-
nally developed to cover primarily the investigational
phase of drug development, but its concepts have been
extended to cover post-marketing (approved) drugs
also (see the E2E guideline, referenced below).
The definitions and recommendations for expedited
reporting developed in this document have largely been
accepted throughout the world. However, some of the
recommendations have been tried and withdrawn (e.g.,
increased frequency reporting in the United States),
inconsistently applied (e.g., breaking the blind), or
never applied (reporting an expedited case to all open
Investigational New Drug Applications [INDs]).
Definitions
Note on Definitions: Most regions have adopted the same,
or similar definitions for these events terms and it is
important for companies to note the differences between
what is defined in ICH versus FDA, EMA, and agencies
world wide. It is within a companies best interest to decide
and define in writing and procedural documents which
definitions they will abide by for consistency amongst
personnel and health care professionals. Ideally, and in a
perfect world, we wouldn’t have even “slight” differences
in these definitions, however it is in the nature of agencies
to interpret terms on their own.
Adverse event or adverse experience (AE): “Any
untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical
product and which does not necessarily have to have a
causal relationship with this treatment.”
Adverse drug reaction (ADR): “In the pre-approval
clinical experience with a new medicinal product or
its new usages, particularly as the therapeutic dose(s)
may not be established: all noxious and unintended
responses to a medicinal product related to any dose
should be considered adverse drug reactions. For
marketed products: A response to a drug which is
noxious and unintended and which occurs at doses
normally used in man for prophylaxis, diagnosis, or
therapy of disease or for modification of physiologi-
cal function.”
Unexpected ADR: “An adverse reaction, the nature or
severity of which is not consistent with the applicable
product information (e.g., Investigator Brochure for an
unapproved investigational medicinal product).” Note
that this applies to non-marketed drugs. This definition
was extended to marketed drugs in the E2D guideline
(see below).