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230 Cobert’s Manual of Drug Safety and Pharmacovigilance
number entered into the study to date, tab-
ulated by age group, gender, and race; the
number whose participation in the study was
completed as planned; and the number who
dropped out of the study for any reason.
If the study has been completed, or if interim
results are known, provide a brief description
of any available study results.
Summary information obtained during the
previous year’s clinical and non-clinical
investigations.
2. A narrative or tabular summary showing the
most frequent and most serious adverse experi-
ences by body system;
3. A summary of all IND 15-day safety reports
submitted during the past year;
4. A list of subjects who died during the investiga-
tion, with the cause of death for each subject;
5. A list of subjects who dropped out during the
investigation in association with any adverse
experience, whether or not it is thought to be
drug related;
6. A brief description of what, if anything, was
obtained that is pertinent for understanding
the drug’s actions, including, for example,
information about dose response, information
from controlled trials, and information about
bio-availability;
7. A list of the pre-clinical studies (including ani-
mal studies) completed or in progress during
the past year and a summary of the major
pre-clinical findings;
8. A summary of any significant manufacturing
or microbiologic changes made during the past
year;
9. A description of the general investigational plan
for the coming year to replace that submitted
one year earlier;
10. If the Investigator Brochure has been revised,
a description of the revision and a copy of the
new brochure;
11. A description of any significant phase I pro-
tocol modifications made during the previous
year and not previously reported to the IND in
a protocol amendment;
12. A brief summary of significant foreign mar-
keting developments with the drug during the
past year, such as approval of marketing in any
country or withdrawal or suspension from mar-
keting in any country.
If the sponsor wishes, it may transfer some or all
duties for clinical trials (including safety) to a third
party, such as another company or a clinical research
organization. In that case, the transfer of obligations
must be described in detail and in writing to the FDA
(21CFR312.52(a)). However, the sponsor retains ulti-
mate accountability.
Other Clinical Trial (IND)
Reporting Issues
Reporting the same 15-day alert case to the IND
and the New Drug Application (NDA):
This issue arises when there is an open IND and
an approved NDA for the same drug. Normally
in simple situations, before NDA approval and
while the IND is open, all 15-day reports are
sent to the IND. After the NDA is approved,
reporting should now, in general, be to the
NDA. There is one situation where there must
be reporting of the same case to both the IND
and the NDA.
Double reporting is required if the serious AE
meets the three IND reporting criteria (serious,
unexpected, possibly related) and is from an
IND study. In this case the 15-day report must
be sent to both the IND and the NDA.
If the serious AE report is from a non-IND
study, then it is reported to the NDA only. Ordi-
narily the SAC or equivalent would recommend
IND reporting, whereas NDA reporting would
be independent of the SAC.
Reporting serious AEs to comparator drugs
and placebos:
Some countries have been requiring the report-
ing of placebo and comparator serious AEs. In
the US, FDA has made it clear that placebo
Expedited and Aggregate Reporting in Clinical Trials 231
cases usually do not meet the four-element
criteria (patient, reporter, drug, AE) because
there is no “drug” and so are not reported.
The EU also, in general, does not want placebo
cases submitted as expedited reports. However,
placebos usually do have excipients and often
“benign” compounds, such as lactose, that
can produce AEs. In addition, in any placebo-
controlled trial, there are usually large num-
bers of AEs seen with placebos. These are
reported at the end of the study in the final
study report.
The sponsor of the trial, especially if the trial is
a multinational trial, must ensure that all regu-
latory reporting requirements are met in each
country where there is a clinical trial site. These
requirements are often different from US/EU/
ICH requirements and may also require local
language reporting for certain serious AEs with
different timelines.
Blinding and unblinding 7-day and 15-day
alert reports:
FDA clarified the issue of unblinding in its
rewrite of the clinical trial reporting rules. They
want all expedited reports submitted to them to
be unblinded.
They have stated as follows (Federal Register/Vol.
75, No. 188/Wednesday, September 29, 2010/Rules and
Regulations. 59947):
“The agency does not believe that unblinding
single or small numbers of informative cases
will compromise the integrity of the study.
However, if patient safety can be assured with-
out breaking the blind, the agency encourages
the sponsor to discuss alternative reporting
arrangements with the appropriate FDA review
division. Any anticipated alternative arrange-
ments to maintain the blind would need to be
described in the protocol, including identifica-
tion of the serious AEs that will not be reported
on an individual basis and the plan for monitor-
ing and reporting results to FDA.”
The EU and the member states generally require
that cases be unblinded before submission:
The ICH E2A guideline, which the FDA also
references and wishes to follow, notes that when
possible and appropriate, the blind should be
maintained for those persons, such as biomet-
rics (statistics) personnel, who are responsi-
ble for data analysis. In large companies, this
often turns out to be difficult to do in practice.
Although statisticians may be blinded, in most
instances when the blind is broken, a Med-
Watch/CIOMS I form/E2B file is created, in
which case it is noted to be the study drug or
control. Usually, serious AE reports are routinely
widely dispersed: to the clinical trial physicians,
monitors, others in the company, the investiga-
tors and the investigational review boards, sub-
sidiaries, clinical research organizations, and
data safety monitoring boards. “Leaks” occur
and the code is inadvertently revealed to those
who are attempting to remain blinded. Thus,
maintaining a “partial” unblinding is difficult.
Note: Some companies, especially those mak-
ing ophthalmology products, do not like to use
the word “blinded” and prefer to use the word
“masked”.
Serious AE reporting after the end of the trial:
There are no clear rules in the US for the dura-
tion of time that serious AEs should be col-
lected and reported in the study report and to
the FDA as expedited reports after a trial ends.
Many use an arbitrary 30-day period after the
patient’s last dose. This may come from the
long-standing clinical medicine tradition of
ascribing post-operative deaths to the surgery
if the death occurred within 30 days of the
operation. Clearly, if a drug has a very short or
very long terminal half-life (e.g., depot formu-
lations), one may use a different time period.
Survival studies (where all patients are followed
until death, such as in cancer trials) present
different issues. Here again, many use a 30-day
limit after the last dose for collection of serious
232 Cobert’s Manual of Drug Safety and Pharmacovigilance
AEs. All deaths, however, should be collected
by the sponsor and sent to the authorities, if
it is believed they meet the criteria for a 7-day
or 15-day report. The issue in survival studies
is that periodic follow-up to see whether the
patients are still alive, one often has serious AEs
reported “in passing”. What to do with these is
an unresolved issue. There is no consensus on
this. Some companies collect and report them.
Others do not.
European Union
Requirements
Expedited Reporting
in Clinical Trials
The expedited reporting in clinical trials is covered in
the Clinical Trials Regulation 536/2014 repealing the
Directive 2001/20/EC. Specifically, the “Detailed guid-
ance on the collection, verification and presentation of
adverse reaction reports arising from clinical trials on
medicinal products for human use” (2011/C 172/01)
covers the subject in great detail. Unlike the situation
in the EU for expedited reporting of post-marketing
SAEs, which is largely harmonized, clinical trial report-
ing may still vary somewhat from country to country
in the EEA.
Key points from the above guidance include the
following:
1. Reportable cases are SUSARs (suspected, unex-
pected, serious adverse reactions).
2. The sponsor and investigator should both make
an independent judgment of causality: “Having
a reasonable suspected causal relationship to an
investigational medicinal product.” (In contrast
to the US, where the sponsor alone is responsible
for assessing causality, either the investigator or
sponsor assessment is used, see Table 2.)
3. Expectedness should be determined using
the Investigator Brochure for non-authorized
(non-MA) products, and the SmPC for autho-
rized ones.
4. In the concerned trial, SUSARs should be reported
for the investigational medicinal product (study
drug, comparators or placebo). For SUSARs in
other trials, refer to the guidance, as the rules are
rather complex and depend on whether there is
a Marketing Authorization (MA) in a member
state.
5. For comparators, the case should be transmitted
to the MA holder of the comparator.
6. Placebo cases normally do not meet the criteria
for expedited reporting unless it is possible the
reaction is due to an excipient or impurity.
7. The ethics committee in some countries may
only receive ICSRs for SUSARs in the concerned
trial in that member state. If so, it is recom-
mended that SUSARs from other member states
and third countries be reported to the ethics
committee (and health authority) at least every
6 months as a line listing and a summary of the
main points. The Executive Summary from the
DSUR may be used as the summary for ethics
committees. Changes in patient risk and new
safety issues as well as changes in the conduct
of the trial should be reported in 15 days to the
committee.
Codes should be broken by the sponsor in
blinded trials before reporting to the ethics
committee and the health authorities. If the
blind break shows the product administered
was the test drug, then it should be an expe-
dited report; if a comparator, it should be
assessed for expectedness against the SmPC
and if unexpected, it should be reported; if
placebo, such events normally don’t satisfy
the requirements for expedited reporting, but
“where after unblinding SUSARs are associ-
ated with placebo, it is the sponsor’s responsi-
bility to report such cases.”
In trials with high morbidity/mortality with
many potential expedited reports, the sponsor
may reach an agreement in advance with the
concerned health agencies concerning SAEs
that are treated as disease-related and not han-
dled as expedited reports. The agreed-on sys-
tem should be noted in the protocol, and it is
recommended that a Data Safety Monitoring
Committee be used.
Expedited and Aggregate Reporting in Clinical Trials 233
Note 1: Even if harmonized at the EU level (see Reg-
ulation 536/2014) with SUSARs, expedited report-
ing for clinical trials can be more requiring in some
EU countries. They actually request, depending on
the clinical development phase or not, the reporting
of all SARs.
Note 2: The rules for reporting expedited reports
in the EU depend on the source of information.
For medicinal products being approved in the EU but
still with ongoing clinical trials, post-marketing SAEs
will follow the Post-approval regulation when clinical
trials SAEs will follow the clinical development reg-
ulation. The same rules apply for aggregate reports:
PSURS are due after the first approval and DSURs are
to be delivered as long as clinical trials are ongoing.
Development Safety Update
Reports
In the EU, sponsors must submit a safety report annu-
ally while a clinical trial is under way. The report should
concisely describe the safety information for one or
more trials. It is known as the Development Safety
Update Report (DSUR) and is loosely based on the
Periodic Safety Update Report (PSUR) that is used for
aggregate reporting in the post-marketing phase. The
DSUR was developed by CIOMS (Report of Working
Group VII) and ICH (E2F Guideline). These two doc-
uments outline the recommended content, format, and
considerations for a DSUR. In some instances there may
be overlap in content between the PSUR and the DSUR,
but each should be prepared as a comprehensive stand-
alone document.
The DSUR is intended to provide a common stan-
dard for an annual aggregate summary report for drugs
in development (pre-marketing and line extensions).
Analysis of safety information on a periodic basis is
essential to protection of subjects enrolled in clinical
trials. It is also critical to inform regulators and other
stakeholders (e.g., ethics committees) at regular inter-
vals about the evolving safety experience with the
investigational product. This is particularly import-
ant if actions are contemplated to address safety con-
cerns. The main focus of the DSUR is on safety data
and the interpretation of those data. Each DSUR should
be concise while at the same time it should give assur-
ance to stakeholders that the investigational program is
being conducted properly.
Note, however, that while all safety issues discov-
ered during the reporting period should be reviewed,
the DSUR should not be the vehicle used to first convey
important new safety information or significant new
safety concerns.
In addition to standardized presentation of safety
information, the DSUR also describes the status of ongo-
ing individual investigations, manufacturing changes,
and overall development status and plans.
The main purpose of the DSUR is to provide a sum-
mary to regulators on an annual basis. It may also be
appropriate to provide a copy to co-development part-
ners or a copy of the Executive Summary (perhaps
supplemented with line listings of serious adverse reac-
tions) to ethics committees or other stakeholders.
See the guidance noted above under EU expedited
reporting for additional details.
The DSUR has four main sections as follows:
1. Introduction
1.1. Background
1.2. Objectives
1.3. Scope of the DSUR
1.4. Relation of the DSUR to the periodic safety
update report
1.5. Recipients of the DSUR
2. General principles
2.1. Single DSUR for an active substance
2.2. Periodicity and DSUR data lock point
2.3. Duration of DSUR submissions
2.4. Responsibilities for preparing and submitting a
DSUR
2.5. DSURs for combination therapies
2.6. Reference safety information
2.7. Format and presentation of DSUR
The recommended table of contents:
Title page
Executive Summary
Table of Contents
1. Introduction
2. Worldwide Marketing Approval Status
234 Cobert’s Manual of Drug Safety and Pharmacovigilance
3. Actions Taken in the Reporting Period for
Safety Reasons
4. Changes to Reference Safety Information
5. Inventory of Clinical Trials Ongoing and
Completed during the Reporting Period
6. Estimated Cumulative Exposure
6.1 Cumulative Subject Exposure in the
Development Programme
6.2 Patient Exposure from Marketing
Experience
7. Data in Line Listings and Summary Tabulations
7.1 Reference Information
7.2 Line Listings of Serious Adverse Reac-
tions during the Reporting Period
7.3 Cumulative Summary Tabulations of
Serious AEs
8. Significant Findings from Clinical Trials
during the Reporting Period
8.1 Completed Clinical Trials
8.2 Ongoing Clinical Trials
8.3 Long-term Follow-up
8.4 Other Therapeutic Use of Investigational
Drug
8.5 New Safety Data Related to Combina-
tion Therapies
9. Safety Findings from Non-interventional
Studies
10. Other Clinical Trial/Study Safety Information
11. Safety Findings from Marketing Experience
12. Non-clinical Data
13. Literature
14. Other DSURs
15. Lack of Efficacy
16. Region-Specific Information
17. Late-Breaking Information
18. Overall Safety Assessment
18.1 Evaluation of the Risks
18.2 Benefit–Risk Considerations
19. Summary of Important Risks
20. Conclusions Appendices to the DSUR
3. Guidance on contents of DSUR
All sections should be completed; when no information
is available, this should be stated.
Title page
The title page of the DSUR should include the following
information:
DSUR number (reports should be numbered
sequentially);
Investigational drug(s);
Reporting period;
Date of the report;
Sponsor(s) name(s) and address(es);
Statement on the confidentiality of the information
included in the DSUR;
A cautionary statement that the DSUR includes
unblinded information, if applicable.
Executive Summary
This section should provide a concise summary of
the important information contained in the report.
Together with the title page, it can serve as a “stand-
alone” document suitable for submission to ethics
committees and other stakeholders, if required by
national or regional laws or regulations. The follow-
ing information should be included in the Executive
Summary:
Introduction — report number and reporting
period;
Investigational drug(s) — mode(s) of action, ther-
apeutic class(es), indication(s), dose(s), route(s) of
administration, formulation(s);
Estimated cumulative exposure of clinical trial
subjects;
Marketing approval(s)? (yes/no) — If yes, number
of countries;
Summary of overall safety assessment (based on
section 18 of the DSUR);
Summary of important risks (based on section 19 of
the DSUR);
Actions taken for safety reasons including signifi-
cant changes to IB;
Conclusions.
Table of Contents
Expedited and Aggregate Reporting in Clinical Trials 235
4. Appendices to this guideline
APPENDIX A — Glossary
APPENDIX B — Examples of tables and table headings
for clinical trial listings
APPENDIX C — Examples of the summary of import-
ant risks.
The DSUR should be submitted on the anniver-
sary of the first authorization in any member state and
within 60 days of the data lockpoint. If there is also an
MA for the product, the Periodic Safety Update Report
(PSUR) and DSUR dates may be harmonized.
Investigators should be informed in writing with
a line listing of SUSARs and a summary of any safety
issues that could adversely affect study subjects.
Each member state in the EU may add more require-
ments in terms of aggregate reporting.
When to Start Collecting
Serious AEs in Trials
Safety data collection starts as soon as the informed
consent is signed and includes the waiting period or
washout period (if there is one), when no study drug is
administered. This concept was particularly noteworthy
in France, where any safety issue that occurred during
the “biomedical research” was reportable. This included
placebo AEs, complications of medical procedures, auto
accidents on the way to the hospital, and so forth. The
idea is that the AEs occurred in regard to the study and
not just the study drug.
In regard to FDA reporting, a serious AE that
occurred before the drug was administered is generally
not related to the study drug and thus does not qual-
ify for a 15-day report. There is at least one situation,
however, where this might not always be the case. Antic-
ipatory nausea and vomiting before cancer chemother-
apy in patients who have already had therapy is rather
common, with an approximate 29% and 11% incidence,
respectively. See the National Cancer Institute review
of this phenomenon at its website (www.cancer.gov).
Thus, one may consider that these serious AEs, which
may be due to classic Pavlovian conditioning, are possi-
bly related to the study or treatment drug even though
it has not yet been taken.
Canadian Requirements
The sponsor of a clinical trial conducted in Canada is
required to notify Health Canada of any serious, unex-
pected, ADR in an expedited manner. Expedited report-
ing in Canada follows the 7-day and 15-day clinical trial
requirements for reporting, whether the case occurred
inside or outside Canada. Each ADR that qualifies for
expedited reporting must be sent to Health Canada
individually.
For causality, the conclusion of either the investi-
gator or the sponsor that there is a “reasonable causal
relationship to the medicinal product” is considered
valid.
Follow-up reports of fatal or life-threatening sus-
pected ADRs must include an assessment of the findings.
The assessment must include an analysis of relevant pre-
vious experience with the same or similar drugs and also
the sponsor position on the importance and implication
of the report.
In addition, Health Canada may request that a spon-
sor submit other safety information at any time while
a clinical trial is ongoing. Such an ad hoc request may
include, for example, a line listing of all serious events,
expected or not.
There may be additional situations that require
rapid sponsor communication with Health Canada on
a safety concern. For example, important new data that
could impact the benefit–risk assessment or that would
lead to protocol changes,
The sponsor must record all AEs in the study (occur-
ring inside or outside Canada), including information
236 Cobert’s Manual of Drug Safety and Pharmacovigilance
that specifies the indication and dosage form at the time
of the AE.
Currently, there is no specific timing in the regula-
tions for the ethics committee (called a Research Ethics
Board in Canada) to receive periodic aggregate reports.
Requirements are thus usually set out by the individual
board in its charter or Standard Operating Procedures
(SOPs). This is undergoing much discussion in Canada.
Since 2015, Health Canada has required an annual
safety review in the format of the ICH DSUR and con-
sistent with the electronic Common Technical Docu-
ment. The DSUR (and the DSUR Checklist) must be
submitted to Health Canada on request. DSURs may
also be provided voluntarily by sponsors when justified
by important new safety information. In addition, the
updated Investigator Brochure must be submitted on an
annual basis. This allows Health Canada to get an over-
view of the drug and trial.
Elsewhere
The requirements for expedited and periodic report-
ing vary significantly from country to country, even
within the EU, and sponsors should check locally and
frequently about reporting requirements, particularly if
there is a study site in that country. It is not uncommon
to have local requirements for annexes that supplement
the “core” DSUR. Also, requirements and submissions
may not always be in written in English. This differs
somewhat from the existing situation for post-marketing
reporting, which is largely harmonized.
Bottom Line
Safety reporting, particularly for expedited reports, has
become exceedingly complex and differs from country
to country in many cases. The regulations and require-
ments are continually changing, and it is likely they will
continue to do so. PV personnel must carefully track
the reporting requirements in all the regions where the
product is being used, studied, developed, approved,
sold, etc.
Q&A
Q: What if during an annual reporting period
there was very little patient data received, or
no data received? Do we still have to submit an
annual progress report such as a DSUR or IND
ASR?
A: Some companies wonder if they are allowed to skip
a reporting period if little to no information has been
received during the reporting period. This could be
due to slow enrollment, delayed clinical trial initiation,
funding, and many other reasons. However, the lack
of, or minimal data, does not absolve a company from
sending in an annual report to the authorities. Addi-
tionally, there are still other components of the annual
report that will change regardless of enrollment data
such as literature and pre-clinical data — so to truly
have “nothing to report” is actually a lazy way to get out
of reporting obligations. It is still required and better to
report the null, or absence of data, than not to report
at all. If a company however wishes to challenge this
requirement, it is in their best interest to communicate
this with the appropriate agencies and potentially deal
with the outcome later.
Q: What if we miss a report? What if the report
is late?
A: Own it. We are all human and even AI will eventu-
ally get it wrong. There will be late reports, there will
be non-compliance, that is known. To an extent, late
reports are generally known to occur and are accept-
able within a specific threshold as long as a company
acknowledges the deficiency and employs continuous
improvement activities. However, how you deal with it
is most important. Once a company has identified that
a report has been distributed late, either to the author-
ities, sites, DSMB, Ethics Committee/IRB, or Investi-
gator, start documenting it and the steps you take to
remedy the situation. This process is generally referred
to as Deviation and Corrective Action and Preventative
Action (CAPA) activities. You will miss a report, or the
report will be sent late, or within the wrong reporting
period — make certain you have operations in place to
identify the error and correct then, then own that there
was a mistake and simply move on.
CHAPTER
237
21
Post-marketing
Spontaneous
ICSR/SAE Reporting
P
ost-marketing spontaneous report-
ing of Individual Case Safety
Reports (ICSRs) is the mainstay of
drug safety at this time, although active
surveillance and other approaches
are being refined and will have an
increasingly important role in protect-
ing patient safety.
General Principles
This chapter focuses on ICSRs that arise after a product
is approved by a regulator for marketing. In this con-
text, the terms post-marketing, post-approval, post-au-
thorization, and post-registration should be considered
synonyms. The requirements for reporting revolve
around various subsets of adverse events and then the
periodic aggregate reporting of the remaining cases
(and some ICSRs already reported) with some degree
of medical analysis. This system, on its face, is quite
extraordinary as it relies on the good will and benefi-
cence of the following:
Healthcare professionals to voluntarily report
untoward events observed with drugs that they
have prescribed or administered, and who are not
compensated for their efforts;
Patients and consumers;
Caregivers and patient advocates; and
Other stakeholders.
This situation is likely to change over the years for
many reasons, including cost and better technology.
The regulations governing post-marketing reporting
are complex, scattered, and only partially harmonized
across regulatory jurisdictions. Various updates and
guidances are published frequently, often changing the
rules significantly in a single jurisdiction. There is no
single source that proactively tracks all changes. The
changes are often, but not always, published in English.
238 Cobert’s Manual of Drug Safety and Pharmacovigilance
(Why countries with their own national languages
should publish their internal rules in English is another
discussion entirely.) When not published in English,
precision, nuances, and cultural context are often lost
in translation.
Post-marketing ICSRs versus
Clinical Trial ICSRs
Although post-marketing New Drug Application (NDA)
or Marketing Authorization Application (MAA) reporting
of SAE cases are conceptually quite similar to pre-market-
ing clinical investigation SAE reports (e.g., IND studies),
there are important differences. The sources and report-
ers of the events are varied as reports are not just coming
from trained clinical trial investigators. Lay language is
often used in reports from patients/consumers/caregivers.
Further, handling and reporting to health agencies are
also somewhat different in different countries. These
challenges are addressed later in this chapter.
As with clinical trial reporting, there is an obligation
for safety reporting after approval of the NDA or MAA.
Post-marketing reporting is usually obligatory after
approval whether or not the drug is actually marketed
(some companies delay marketing for operational or
seasonal reasons). In clinical trials, AEs are reported by
investigators who are health professionals and usually
have a relationship with the company (e.g., sponsored
trials). Thus, cooperation and complete medical reports
from a healthcare professional are usually ensured, par-
ticularly for SAEs in clinical trials. Under governmental
regulations, safety reporting is obligatory for the inves-
tigator and the sponsor.
The post-marketing period, however, is quite differ-
ent. Reports may come from many sources, including
patients, families of patients, healthcare professionals,
sales representatives, literature reports, news reports,
health authorities, the Internet, blogs, social media, poi-
son control centers, other pharmaceutical companies,
lawyers, and more. Products may be used off label. In
most instances, reporting is voluntary for everyone
except pharmaceutical companies and rests on the
goodwill of the reporters. However, sometimes, patients
who report AEs are upset that the AE happened at all.
They may assume that drugs are safe and this AE should
not have happened. At least in the United States, they
often want their money back and, in fact, may have
called the company not to report the AE but rather to
get a refund or discount coupon.
Healthcare professionals often contact the health
agency or the pharmaceutical company to report an AE
and are not quite aware that the company, obliged to
follow-up and report the case to the authorities, will do
extensive follow-up and request copies of reports from
the physician’s office, the hospital, the laboratory, and
even the ambulance service. Busy pharmacists, nurses,
or physicians often do not realize what they are getting
into when they simply called to do their duty by mak-
ing a “quick” report of an AE. They did not want to
get burdened down with pulling records (perhaps from
multiple sources), protecting patient privacy, and send-
ing them to the company.
Report quality is also an issue compared with clin-
ical trial reports, as the quality of the post-marketing
reports is quite variable, especially when reported by
non-medical people. Consumer reports should have
follow-up attempted with the treating physician where
possible. The problem is more difficult if the patient
used a self-prescribed over-the-counter (OTC) prod-
uct or herbal preparation; there may be no physician or
pharmacist involved at all.
The four elements or criteria for a valid ICSR (some-
times called the minimal dataset for reportability) are as
follows:
1. An identifiable patient;
2. An identifiable reporter;
3. A suspect drug(s); and
4. An AE (or fatal outcome if no AE is reported
other than “found dead”).
If these four elements are present, then the case
is considered valid and reportable to Health Authori-
ties (e.g., Food and Drug Administration, European
Medicines Agency, Health Canada, Pharmaceuticals
and Medical Devices Agency in Japan, etc.). If they are
not, the company should make due diligence efforts to
obtain the missing data. The data should be stored in a
secure, electronic database.
Post-marketing Spontaneous ICSR/SAE Reporting 239
An identifiable patient usually means one or more
identifiers are present: age, sex, initials, name, date of
birth, and so on. Vague reports such as “I heard there
was a patient or two upstate who took drug X and had
a stroke” or “a few people had strokes” are not specific
enough to meet the criteria for identifiable patient.
“A man” or “a young girl” or “six men had strokes” are
sufficient to be considered identifiable. Some people
feel that AE with an occurrence date, indirectly means
an identifiable patient.
An identifiable reporter is usually clearer. It may
be the patient or a family member. As a rule of thumb,
an identifiable reporter should be one who can be con-
tacted. Thus, an e-mail AE report where there is no infor-
mation on the sender other than the properly formatted
e-mail address would be a valid reporter because one
can respond to the e-mail and get follow-up. However,
procedures should be developed to determine patient
and reporter identifiability and requirements, including
for posts on company-sponsored websites.
The suspect drug is also usually not a problem.
However, issues do occur as follows:
1. Occasionally, someone will send in an AE report
and make the comment, “I don’t think this is
due to your drug but thought I should report it
anyway, just in case.” This should still be con-
sidered the suspect drug (unless another one is
noted) and the reporter’s comment noted in the
narrative.
2. If it is clear that the drug is the product of
another company (e.g., same chemical entity
but different manufacturer, whether branded or
generic), the case should be sent within 5 days
to that manufacturer or company if it is located
in the United States. Elsewhere rules vary, but
in general, the case should go to the manufac-
turer/MAH (a PV department policy on how and
when to inform competitors can be useful — tri-
age of clinical trial and post-marketing reports
to competitors may be different.) If, however, it
is unclear whether it is the company’s marketed
product or another manufacturer’s product, then
the company must process it as if it were clearly
its own product. The lack of clear “ownership”
and product identification should be noted in the
report.
3. Different formulations of the same active moiety
must be entered into the database and reported,
as appropriate, unless the product is clearly
found to be from another company. Thus, a top-
ical version of a company’s product made by
another company (but unclear which one) needs
to be reported.
4. Combination products that contain the active
moiety should also be reported.
5. An audit trail should be kept for all ICSRs triaged
to competitors.
The identifiable AE is also usually clear and relates
to any untoward event or “bad thing”. The AE could
include signs, laboratory abnormalities, symptoms,
or diseases. More general terms like experienced
unspecified injury or irreparable damages should be
excluded, but follow-up should be attempted. Fatal
outcome with no AE should be considered reportable
(“found dead in bed”). This is the only instance in
which an outcome is considered an AE. Death is an
outcome and not an AE unless there is no other AE
reported.
One should also be sure to distinguish medication
errors and product quality issues. Sometimes two or
more things may occur in the same report, as in this
scenario: “The tablet was blue instead of green and
smelled funny; I took two instead of one and then had
a bad headache. And I want my money back and I have
a question.” The product quality, medication error, AE,
question, and refund issues should each be handled by
the appropriate personnel in the company.
In most countries, the company (“applicant”,
“sponsor”, or MAH, IND holder, NDA holder) must
report each AE that is serious and unexpected (i.e., not
included in the regulator-approved labeling (= Package
Insert for the United States or the product monograph
in many other countries, etc.), whether domestic or for-
eign, within 15 calendar days of initial receipt of the
information. For the EU, all serious reports should be
expedited to EudraVigilance. Note that this is different
from the criteria used for clinical trial reporting, which,
in most countries, requires three criteria (serious, unex-
pected, possibly related to the drug).