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160 Cobert’s Manual of Drug Safety and Pharmacovigilance
teleconferences, face-to-face, etc.). The chosen pro-
cesses and tools must allow a strong support and flexi-
bility from DMC members; urgent ad-hoc meetings for
any important safety issue must be possible to quickly
bring an accurate proposal to the sponsor.
A key component (though not “officially” a voting
member) of the DMC is the statistician or statistical
group, who prepares, analyzes, and presents interim
trial results to the DMC. The statistician may be from
the company or sponsor or may be from an external
CRO or independent consulting firm, but must not be
engaged in the actual conduct of the study. The statisti-
cian will usually have the blinding key and will unblind
study results (see below).
Each DMC meeting usually has an initial open ses-
sion, followed by a closed session and then a wrap-up
open session. At the initial “open” session with DMC
and the sponsor, non-confidential matters are dis-
cussed, including the clinical trial program, the status
of recruitment, baseline patient characteristics, ineligi-
bility rate, accuracy and timeliness of data submissions,
and other administrative data and plans. The closed
session is attended by only the DMC members and the
“independent” statistician who prepared and is present-
ing the interim analyses to the DMC. After the closed
session, a wrap-up open session may be held with the
sponsor to relay any recommendations from the DMC.
The DMC has the option of conducting an “executive”
session with no participants other than DMC members
(that is, no sponsor representatives at all), though this
is usually not needed.
There has been controversy over whether the DMC
should see blinded or unblinded data. Most feel that
DMC members should have access to unblinded data
to ensure their ability to make accurate risk–benefit
assessments. If this is the case, then printed reports of
unblinded interim analyses should be supplied to the
DMC members several days (at least) before the meet-
ing to allow for adequate review of the information.
Sometimes a partial unblinding is done, whereby treat-
ment codes are given for each treatment group (e.g.,
drug X, drug Y, rather than the names of the drugs). The
sponsor should supply the data in a reviewable form.
For large studies, some sponsors provide the DMC
with listings of individual patients’ data, often in a very
non-user-friendly way. When there are hundreds or
thousands of patients each with multiple labs, exams,
and so forth, totaling millions of data points over thou-
sands of pages, it is hard to “eyeball” the data and find
trends or issues. These reports and underlying data can
also be supplied in digital format. Excellent software
is available for examining trends and outliers. Many
DMCs also want to see the case report forms for all seri-
ous cases or at least all expedited cases.
A terminology note: Companies that make ophthalmo-
logic products usually do not like to use the word “blinded”
and prefer to use the word “masked”. So, studies are not
blinded but masked.
There is a “statistical downside” to multiple reviews
of interim data that the sponsor may perform in some
studies, namely, that repeated statistical comparisons
of event rates between the treated and control groups
increases the “false-positive” rate if p values are not
adjusted for multiple testing. To put it another way, the
more interim data reviews that are done, the more likely
that a type I error will be found. At the p < 0.05 level,
the probability of nominally significant results occur-
ring with three interim analyses is about 10% greater,
and with 10 interim analyses about 20% greater.
1
To get
around this problem, there are various options available
that basically increase the p value required for signif-
icance (e.g., requiring a level of 0.018 at each interim
and final analysis or 0.001 at each interim analysis
and 0.05 at the final analysis). No matter what statis-
tical techniques are used, the DMC must not rely on
statistical analyses alone to reach a conclusion. Clinical
judgment must also be used to evaluate the safety and
efficacy information. Thus, a DMC should have one or
more experienced clinicians (physicians) to make clin-
ical judgments.
The DMC will compare AE rates in each treatment
arm to see whether there are any major imbalances of
concern, and which seem to be due to the intervention
rather than the disease or confounding factors (e.g.,
all the patients in some Northern Hemisphere centers
come down with a seasonal influenza). The DMC may
also want to see specific patient information for criti-
cal or important cases (e.g., SUSARs, acute liver failure,
all patients where the blind is broken by the sponsor
1
See McPherson, Statistics: the problem of examining accumulating
data more than once, New Engl J Med 1978; 290: 501–502.
Data Monitoring Committees and Investigational Review Boards/Ethics Committees 161
or investigator for safety reasons). Again, this calls for
good software and reporting tools to allow the DMC to
visualize the data it needs.
All meetings should have minutes and kept as a
record for the TMF at study closure. This can be tricky
as there may be unblinded discussions and sections of
the meeting. If the minutes are circulated to company
and external individuals, unblinded information must
not be included in the minutes. These unblinded dis-
cussions may need to be excluded from the minutes
or a separate set of “unblinded” minutes may be kept
within the DMC. Some DMCs write “minimalist” min-
utes in which only the topics and options (as noted in
the next paragraph here) are included. Discussions are
not included.
The DMC has three options after each meeting as
follows:
1. Continue the trial unmodified;
2. Modify the trial (Make recommendations on
clinical development):
a. Drop a treatment arm or sub-group;
b. Modify the treatment dose/schedule;
c. Add additional safety tests (e.g., electrocardio-
grams) at screening or during the trial;
d. Modify consent/Investigators’ Brochure;
3. Terminate the trial early due to the following:
Serious safety issues;
a. The efficacy question has been answered and
the results are truly compelling, with the risk
of a false-positive conclusion acceptably low;
b. The hypothesis is no longer relevant or the
hypothesized benefit cannot be achieved.
There are no rigid stopping rules. Rather, the com-
mittee must exercise judgment. General rules of thumb
have evolved. It is usually appropriate to demand less
rigorous proof of harm to justify early termination than
would be appropriate for a finding of benefit. The best is
probably to develop general stopping rules in the DMC
charter but also keep the door open for unanticipated
signals which would justify further assessment and
potential stopping.
Interestingly, there is an ongoing and probably
unanswerable ethical conflict with DMCs, namely,
where does their primary responsibility lie?
Perspective 1: The DMC’s primary responsibility
is to the specific patients enrolled in the trial. This
implies that the DMC should stop the trial early if
further results are unlikely to change the conclu-
sion based on interim data. That is, do not put the
individual patients at further risk or subject them to
placebo for longer than the minimal time necessary.
Perspective 2: The DMC’s primary responsibility
is to the entire “patient horizon” and the practice of
medicine in general. In this case, the DMC would
stop the trial early only if the results are sufficiently
persuasive to effect changes in medical practice
based on limited data.
No single answer fits all cases.
The DMC is usually advisory to the sponsor, and
the sponsor may reject the DMC’s comments, though
this will obviously produce controversy and multiple
ethical issues. The DMC results must be communicated
to the health agency and the IRBs in any case.
In practice, for large multi-year, multi-center studies,
DMCs have proved very useful when well-constituted
and well-run. Logistics can be costly and complex if
there are thousands of patients and several studies
going on at the same time. It is likely that more and
more DMCs will be used. Some are even considering
DMCs or their equivalent in the post-marketing setting,
looking at the spontaneous data coming into the spon-
sor or Marketing Authorization Holder (MAH). Some
have used DMCs in early phase I trials also, but this is
very uncommon.
2
Investigational Review
Boards/Ethics Committees
Clinical trials require formal, external, neutral commit-
tees to review the protocol and course of the study as
well as other aspects of the study. These are called either
2
For more information on DMCs, refer to the following articles:
Shein-Chung Chow, Ralph Corey, Min Lin, On the independence of
data monitoring committee in adaptive design clinical trials, J Bio-
pharm Statist 2012; 22(4): 853–867; Ellenberg SS, Culbertson R, Gil-
len DL, Goodman S, Schrandt S, Zirkle M, Data monitoring commit-
tees for pragmatic clinical trials, Clin Trials 2015; 12(5): 530–536.
162 Cobert’s Manual of Drug Safety and Pharmacovigilance
Investigational Review Boards (IRBs) or Ethics Com-
mittees (ECs). The rules are fairly complex and vary
a bit in different regions, but the concepts are all the
same: patient protection and good science. These com-
mittees may be attached to medical institutions (e.g.,
hospitals, medical schools) or may be unattached and
free-standing, which has led to some controversy. Some
may be “central” (e.g., in the European Union covering
all sites in one country or in the United States covering
all sites) or local. Some studies use a mixture of both
local and central IRBs. There are some US-based IRBs
that provide service-for-a-fee.
ICH addressed the issue in their 2016 guideline:
Integrated Addendum to ICH E6(R1): Guideline for
Good Clinical Practice E6(R2) (www.ich.org).
The EU addressed Ethics Committees in several
places, including Directive 2001/20/EC and EudraLex
Volume 10 Clinical Trials Guidelines. There are exten-
sive FDA regulations and guidances for IRBs to follow
regarding their requirements and obligations in clinical
studies. See the “Detailed guidance on the application
format and documentation to be submitted in an appli-
cation for an Ethics Committee opinion on the clinical
trial on medicinal products for human use”.
The key US regulations are found at 21CFR56.109
(IRB on the review of research). Other requirements
include 21 CFR 50.25, which covers protection of
human subjects. An FDA summary page clinical trials
and human subject protection can be found at: (https://
www.fda.gov/scienceresearch/specialtopics/running
clinicaltrials/default.htm).
Finally, in August 2016, the FDA issued a draft
Guidance for IRBs on written procedures (https://www.
fda.gov/downloads/regulatoryinformation/guidances/
ucm512761.pdf). There are multiple other guidances
on the FDA website which should be referred to cover-
ing various aspects of IRBs. The IRB is now expected to
be sure of the following:
1. Risks to the subjects are minimized;
2. Risks to subjects are reasonable in relation to
anticipated benefits, if any, to subjects, and to
the importance of the knowledge that may be
expected to result;
3. Selection of subjects is equitable;
4. Informed consent will be sought and appropri-
ately documented;
5. Where appropriate, the research plan adequately
provides for monitoring the data collected, to
ensure the safety of subjects;
6. Where appropriate, there are adequate provisions
to protect the privacy of subjects and to maintain
the confidentiality of data;
7. Appropriate additional safeguards are included
to protect vulnerable subjects; and
8. Where the study involves children, the research
complies with 21CFR50, Subpart D.
FDA regularly audits IRBs and FDA has issued
Warning Letters in instances when the IRB was not
meeting its obligation to protect patients.
In the EU, the guideline specifies, “The responsibil-
ity of an Ethics Committee is to ensure the protection
of the rights, safety and well-being of human subjects
involved in the clinical trial.”
The IRBs and Ethics Committees must review and
approve clinical trial protocols to ensure the maximum
possible patient protection. This includes a review of
the protocol, informed consent, and other aspects of the
safety procedures in these trials before the trial starts, as
well as maintaining ongoing monitoring of the conduct
and results of the trial at least yearly.
These requirements oblige investigators and spon-
sors to submit certain serious AEs to the IRBs/Ethics
Committees either as they occur or in aggregate sum-
mary reports. A key controversy revolves around what
data are to be sent to the IRBs and Ethics Committees.
In the past, every expedited report and follow-up case
was sent. This proved to be logistically problematic for
the investigators and IRBs as follow-up reports often
contained uninformative data (e.g., correction of height
or weight). The health agencies have clarified this situ-
ation to a degree and now recommend aggregate report-
ing and line listings sent periodically, e.g., annually.
Individual expedited cases are still required but
follow-up reports are usually not sent unless they are
Data Monitoring Committees and Investigational Review Boards/Ethics Committees 163
medically important. It is useful to discuss with the
IRBs and Ethics Committees before starting the study
what they wish to receive and when.
For further information, the reader is referred to
these documents as well as documents in each country
where a trial is being held. This is a complex and chang-
ing area as health agencies and the public are becoming
increasingly concerned about patient protection.
Frequently Asked Questions
Q: Does it make sense to set up one single
DMC for the whole clinical development pro-
gram rather than one per important trial? This
would be similar to the FDA concept of a Safety
Assessment Committee (SAC).
A: This is a sponsor’s policy/decision, although Health
Agencies expect a sponsor to demonstrate due diligence
across a whole program conducted under an IND. For
very large international development projects, with tri-
als in many countries, requesting DMC members to
review systematically all safety data can be problematic
because of a heavy amount of data to review. Neverthe-
less, if a DMC is covering part of the trials, in the case
of an important safety issue, providing safety data from
other trials to the DMC to ensure an accurate assess-
ment should be considered. One of the authors served
on a DMC that covered about 10 or 12 trials over several
years. They overlapped for certain periods, and we often
saw data from 6 to 8 trials. This was feasible for the group
but did require a lot of time for data review. The SAC con-
cept now seems to be a good fit for a situation like this.
Q: With the roles and responsibilities of the
IRB/Ethics Committee overlapping the duties
of the DMC, do we really need a DMC?
A: IRB/EC are required (by regulation) to approve the
protocol and then should become an active stakeholder
in case of a safety issue. Although the roles of the IRB/
EC and DMC overlap, the DMC works much more in
“real time” whereas the IRB/EC often sees the data in
aggregate or in summary form at intervals. IRB/ECs
also may work with many studies and cannot spend as
much time and focus on a single safety issue from one
of the many studies, perhaps only annually. The DMC
can also call for additional data and analyses more easily
and more quickly than the IRB/EC. In addition, the IRB/
EC can usually stop a study whereas the DMC usually
only makes recommendations to the sponsor and can-
not actually stop a study itself. Finally, in general, in
medicine, the more eyes that look at a patient or a study
or data, the better.
Q: Isn’t having Key Opinion Leaders (KOLs)/
experts in a DMC a way to transfer the respon-
sibility for any decision from the sponsor to
the DMC?
A: From the legal and regulatory viewpoint, the spon-
sor remains THE responsible person/entity for the trial
and is viewed that way by the regulatory agencies. From
a practical viewpoint, any decision or recommendation
made by the DMC, the sponsor is more or less “forced”
to follow it.
In other words, setting up a DMC is an important
decision and choosing the DMC members is a key part
of the process. Picking members who are biased or who
are expected to make only favorable decisions is a dan-
gerous policy. Choosing “friends” of some employees
can be risky. As an example, having DMC members
not experienced in the clinical development field can
become problematic if they force a decision which is not
appropriate or if they miss a safety issue that the experts
would have picked up.
It is unfortunate that many financial and stock
analysts follow DMCs decisions and make buy and
sell decisions based on this. They usually do not
understand or have all the data. These observers can
have a strong impact on a start-up company’s value
and financial stability. It is, therefore, critical to agree
on clear roles and responsibilities between the spon-
sor and the DMC before the DMC kick-off meeting.
Moreover, the roles, responsibilities and limits must
be included in the charter and agreed on by all parties.
DMC members should not talk to the press or others
who might benefit from DMC knowledge about the
situation; confidentially aspects must be specified in
the contract.
CHAPTER
165
14
How an Individual Case
Safety Report (ICSR) is
Handled from Start to
Finish
T
his chapter traces an adverse
event (AE) through its course in
a company from start to finish.
The focus of this chapter is on process.
A typical case handling process is out-
lined below. Each step varies from com-
pany to company, but all such processes
must have written procedures for data
receipt, case assessment for expedited
reporting, data entry, coding and data
review by medical professionals (ini-
tially often by a nurse or pharmacist),
and a final data review by a physician.
The processes illustrated here are not
necessarily better than other processes
used in the industry. Nor is there a
mandated process from the U.S. Food
and Drug Administration (FDA), Euro-
pean Medicines Agency (EMA), or any
other health authority. Rather, which-
ever process is implemented, it should
ensure a smooth workflow and full
compliance with all laws, directives,
regulations, and guidances.
Introduction
The mission of the AE processing unit is to ensure that
all complaint cases (including AEs, product quality
problems, tampering, packaging problems, counter-
feits, etc.) are processed in a timely and accurate man-
ner, such that all cases are of high quality and sent to
the appropriate departments within the company, to
166 Cobert’s Manual of Drug Safety and Pharmacovigilance
business partners, and to health authorities on time.
The goals are to ensure prompt handling and submis-
sion of expedited reports, periodic pre-marketing (e.g.,
Development Safety Update Reports (DSURs)) and post-
marketing (e.g., Periodic Safety Update Reports (PSURs)
reports and any other obligatory reports. Because late
reports to health agencies and business partners are
usually easily and immediately noted, this statistic
tends to be the one that drug safety groups, manage-
ment, and health authorities look at to “grade” compa-
nies. The goal is 100% compliance all the time, but the
reality is that, in an imperfect world, 100% is not always
attained. However, nobody will officially write or say
this or give an acceptable error rate. More importantly,
cases that are late should not be late by very long or
for the same reason twice. A root cause analysis to find
errors, failures to follow the standard operating proce-
dures, and so on should be performed and corrective
actions put in place to prevent repetition.
Many companies put maximal effort into keep-
ing the expedited report score near 100%, often at the
expense of case quality or delays in the processing of
non-expedited cases — even though no one ever admits
to decreases in quality. Companies often build up back-
logs of unprocessed or partially processed cases when
resources are insufficient to be fully compliant with both
expedited and non-expedited cases. Sooner or later, this
situation produces a disastrous result unless corrective
actions are applied and modified processes are put in
place. Adjusted processes must be workable and actu-
ally followed. Everything has to be done correctly.
There are many ways to handle cases. In some com-
panies, there is ownership by an individual drug safety
specialist (e.g., a nurse or pharmacist), who is respon-
sible for the completion of the case from start to fin-
ish, making sure that any other personnel involved in
processing the case (e.g., medical reviewers) handle the
case and return it to the specialist who “owns” it. Other
companies have less individual ownership of a case and
instead move a case from task to task in the workflow,
with a separate “pool” of workers responsible for a par-
ticular step, such as one group that just performs data
entry, another that just does coding, and another that
just writes narratives. There are many variations on
these themes.
AE Sources and Arrival in the
Safety Department
Serious adverse events (SAEs) and non-serious AEs may
arrive in a company from multiple sources (sometimes
referred to as “feeder groups”). Standard operating pro-
cedures must be in place to ensure that these AEs arrive
in a timely manner (usually 1–2 days) in the drug safety
department if they first arrive elsewhere in the company
or at a partner company.
Spontaneous SAEs and non-serious cases arrive by
telephone (the most common route of arrival in many
companies); websites; electronically; e-mail; snail mail;
fax; reports to sales representatives; reports to other
company employees, agents, or contractors; the legal
department; health authorities (e.g., FDA, EMA/ EU
Agencies, MHRA, Health Canada, etc.); other com-
panies who receive AEs on their own drugs in which
one of their drugs is involved; and other miscellaneous
sources such as newspaper, social media, or TV stories.
They are received primarily from consumers, health-
care professionals, and lawyers. It should be kept in
mind that such AEs may arrive at any location in the
company, such as manufacturing facilities (especially
if the product package says something to the effect of,
“Manufactured by XXX Pharma in YYY City”, or if an
address or phone number is on the package or patient
information), subsidiaries and affiliates, contractors,
outsourcers, and business partners with whom safety
data exchange agreements are in place.
Safety department call centers are usually staffed to
receive phone calls from a particular region in a certain
language. Usually, they cover a whole country but not
more than one country, because labeling, indications,
precautions, and warnings may differ from country to
country and the appropriate information must be given
to residents of the appropriate country. There may also
be language issues. For example, any phone center cov-
ering Canada must be able to respond in English or
French. In the US, though not required by law, many
phone centers have Spanish-speaking personnel avail-
able in addition to English speakers. Phone centers
may be available Monday through Friday during busi-
ness hours or sometimes 24 hours a day, 7 days a week.
How an Individual Case Safety Report (ICSR) is Handled from Start to Finish 167
Multiple time zones must also be taken into account
for geographically large countries (e.g. Canada, China,
Russia, US). Call centers may be kept in-house or out-
sourced to companies that specialize in handling med-
ical phone calls. These call centers may be within the
country or far away (e.g., India, Philippines, and other
English-speaking countries are now handling calls from
the US and Canada in many cases). Interestingly, some
call centers covering English language callers are now
being placed in non-native English-speaking countries.
Call centers should be set up to receive calls from
consumers, patients, physicians, and other healthcare
providers. They usually cover questions about the prod-
ucts; requests for reimbursement; and reporting of AEs,
product quality defects, and problems and emergencies
regarding the drug, including tampering, counterfeit-
ing, and overdoses. For clinical trial (non-marketed)
products, the call center may need to have an emer-
gency code break to handle an acute AE. The call cen-
ter must be set up to ensure that all AEs and quality
complaints are captured and sent to the appropriate
departments for handling (e.g., the AEs to drug safety
and the quality complaints to manufacturing). In addi-
tion, any questions or requests for reimbursement must
be handled rapidly and correctly. Callers who are com-
plaining or agitated must also be handled carefully and
diplomatically. Thus, a clear protocol must be set up to
ensure that customers are served quickly and well, that
their requests are met, and that all AEs and complaints
are captured. The call should be picked up on the first
or second ring, the caller should not be kept on hold
for any significant length of time, and the caller should
not have to give his or her name, address, and product
issue more than once. The caller should not be bounced
to multiple departments. Professional call centers are
able to track very precise metrics measuring all of these
factors.
All this requires a well-thought-out system to han-
dle all issues (especially when a caller has multiple
issues: “I took your pill, which was supposed to be red
but was blue; it smelled bad; I developed a headache;
I want my money back; and I have a question.”). The
decision about when to have medically trained per-
sonnel take the call must be clarified: should all calls
come directly to a nurse or pharmacist or should there
be some level of non-medical screening before sending
the call to the healthcare professional? If non-medical
professionals are used, an algorithm or script is often
used to ensure that no incorrect information is given
to the caller. In addition, the priorities must be consid-
ered: should the AE and quality complaint be handled
first (most drug safety people would say yes to this but
marketers might not)? Because there are multiple com-
pany stakeholders involved (drug safety, information
technology, product quality, marketing, reimbursement,
medical information, etc.), the development of the call
center is complex and expensive.
Other sources of AEs (and follow-up) may include
the following:
Clinical studies: Clinical study events may
come in from the company’s clinical research and
clinical pharmacology departments, as well as any
other group that might run studies (sometimes
unbeknownst to the drug safety department).
Such groups might be in marketing, subsidiaries,
affiliates, market research, pharmacoepidemiol-
ogy, pharmacoeconomics, or other companies that
are studying the drug with your company or are
studying the drug without your company’s con-
sent and knowledge. AEs may also arrive from
contract research organizations.
Often, much to the chagrin of the safety group,
the first awareness that a study is being run in some
far-off outpost of the company is the arrival of a
serious AE. In the most egregious of such cases, an
event may arrive for a drug that the safety depart-
ment does not even know to be owned, studied, or
sold by the company. It might, for example, be stud-
ied (or marketed) only in one subsidiary, affiliate, or
a partner far away.
Legal: Lawsuits are sometimes the unfortunate
first notification to a company that there is a seri-
ous AE. These cases usually come in through the
legal department, which should be sensitized to
the fact that they must not only defend a lawsuit,
but also report the AEs to the drug safety depart-
ment. These AEs are usually on marketed products
but may sometimes involve clinical trial subjects.
Rarely, a company may be notified of an issue by the
168 Cobert’s Manual of Drug Safety and Pharmacovigilance
arrival of a subpoena to provide evidence in a law-
suit to which the company is not a party, such as a
malpractice case in which there is also a drug issue.
Normally, the receipt of AEs via lawsuits is limited,
but in certain circumstances, such cases may be
voluminous, especially in class action lawsuits in
the US.
Health agencies: Many health authorities send
to or allow companies (and sometimes the public)
access to specific AE cases. The FDA has a program
(MedWatch to Manufacturer) in which it sends
copies of spontaneously received reports of serious
AEs on newly approved products (new molecular
entities or “important new biologics”) to the man-
ufacturer of the product. The drug must be a new
chemical entity. This program lasts 3–4 years and
is done at the request of the manufacturer. These
reports do not have to be resubmitted to the FDA
by the company unless additional information is
obtained, but they may have to be submitted to
health authorities outside the US if the drug is mar-
keted elsewhere. Health Canada allows the public
to search their database, and the FDA has a public
dashboard for safety data that can be used to sort
and review FAERS data.
Literature reports: US and EU regulations
require that companies periodically (e.g., weekly
EU GVP module VI) search the medical literature
for serious AEs. Such publications are usually on
marketed products but may occasionally include
serious AEs from clinical trials of new uses for old
drugs unknown to the company. Once a drug is on
the market, however, nearly anyone may do a clin-
ical trial using the drug (following, of course, reg-
ulations, consent, ethics committee approval, etc.)
without telling the company. Reports in the liter-
ature may be of serious AEs or non-serious AEs,
though the former predominate. In oncology, coop-
erative groups may use marketed drugs in clinical
trials (alone or in combination) for new indications
or at different doses or schedules from the approved
labeling.
Stimulated reports: Many companies have “cus-
tomer engagement programs”, e.g., patient support
programs or disease management programs, etc.,
in which company or outside service companies’
representatives (e.g., nurses, physicians) contact
patients to encourage them to continue to take
their medications and give support regarding dos-
ing, AEs, and so forth. During the course of discus-
sions, AE reports may be obtained. If the company
is involved in these support programs (internally or
outsourced), a mechanism and process must be cre-
ated to ensure that all AEs reach the company in a
timely manner and are handled appropriately. Other
programs such as speaker programs, named-patient
programs, and compassionate use may also stimu-
late reports.
Other sources of AEs include poison control cen-
ters and company and external internet sites (blogs,
social media, etc.). In general, the company is not
required to troll the internet to look for such AEs,
though it must track and capture such AEs of which
it becomes aware and, of course, AEs from its own
websites (or websites funded by the company). If
a drug is reported to another company either by
mistake or expressly (e.g., a marketing competitor,
another company doing a trial with your drug or
in which your drug is a suspect medication in an
ICSR), SAE reports may arrive unannounced from
other companies on your drug. These cases may be
problematic as they may arrive as completed, ano-
nymized ICSRs from the other company. Because of
the anonymization, follow-up, as a practical matter,
will usually be impossible.
Electronic receipt of ICSRs by E2B (or customized)
formats is common and the company should have
systems in place allowing receipt (and transmis-
sion) of such cases. This includes the most current
E2B version as well as the previous version. Note
that follow-up information may arrive by a differ-
ent means from the original report (e.g., an initial
phone report may be followed by a written e-mail/
PDF or snail mail communication).
Triage
Upon arrival, by whatever route, of the case data in the
drug safety department, it must be properly classified
for processing. Whether the report arrives electronically
with structured data or not, it must be date-stamped
upon entry into the drug safety department. For paper
cases, this is a manual rubber stamp with the date and
How an Individual Case Safety Report (ICSR) is Handled from Start to Finish 169
time of arrival. For electronic reports, presumably
whatever system is used automatically date stamps the
information. Note that this then forces day 0 to be the
electronic time stamp. In “the old days”, if a case is
delivered on Saturday but not opened in the mailroom
until Monday, the date stamp and day 0 are Monday. In
the “modern electronic world” if a similar case arrives
by fax or other electronic means and is date-stamped
electronically as Saturday, that is day 0. Follow-up
information must also be handled expeditiously.
Every single report that is received should be con-
sidered an expedited report until proven otherwise.
Thus, the initial triage should be to determine whether
the report needs urgent processing to be transmitted
to the health authorities, others in the company (e.g.,
manufacturing for quality issues), or business partners
as an expedited report. The triage should be done by
someone with a medical skill set to make an accurate
determination. Many companies have nurses and phar-
macists in this critical role. Triage or case assessment
should be standardized. Many companies use dedicated
personnel for this function and others rotate staff in to
do the triage. For difficult or controversial cases, the
triage personnel may request assistance from the drug
safety physicians.
Triage should cover, at the least, the following:
1. Which drug(s) is(are) involved? Is it our drug?
2. Case type: spontaneous, clinical trial, stimulated,
other?
3. Are the four elements of a valid case (reporter,
patient, AE, drug) present and identifiable?
4. Is the AE serious or non-serious?
5. Is there evidence or plausibility for a causal rela-
tionship with the suspected drug (for serious
clinical trial cases, not for spontaneous cases)?
6. Is the AE expected (labeled) for serious and non-
serious cases?
7. Which reports should be expedited?
7-day clinical trial report: serious and death/
life-threatening (at presentation), unlabeled,
and associated (possibly caused by) with the
drug in question;
15-day clinical trial and solicited report: seri-
ous, unlabeled, and associated with (possibly
caused by) the drug in question;
15-day post-marketing report: serious and unla-
beled (no causality determination required);
Other reports requiring urgent processing,
such as those cases requested by the health
agency (“heightened surveillance”) to be
transmitted to them in an expedited fashion,
but that do not meet the formal criteria above
or where contracts with a business partner
require rapid transmittal.
8. Pregnancy cases (some companies examine for
pregnancy cases at triage and others do it later on
in the case processing);
With an accompanying AE (serious or non-
serious);
No accompanying AE (serious or non-serious);
9. Product quality complaints (if handled in drug
safety) — urgent or non-urgent.
These criteria may be built into an electronic algo-
rithm in the workflow component of the safety data-
base or may be handled with a paper log and tracking
form for each case. Some databases have “portals”, or
desktop displays, of all new and ongoing cases, which
can be customized for each employee so that a person
knows which cases he or she owns, as well as their
workflow status. Manager-level screens may show all
the cases in the staff reporting to that manager. Some
companies also log all cases into a spreadsheet to track
them and ensure that they are not lost in transit within
the safety department or at the time of “hand-offs” at
each step of the case. In particular, “incomplete cases”,
or those that do not yet have the four required elements
for a valid case but may later on, should be tracked to
ensure they are not forgotten or do not “slip through
the cracks.” A case number should be assigned at this
point. This may be a screening case number or the
definitive case number assigned by the safety database.
For E2B cases, this will include the worldwide ID num-
ber. Note that if an “informal” spreadsheet is used to
track cases or potential cases, it is subject to audit or
inspection and should be secured so that it cannot be
altered or changed inappropriately. In general, using
such informal spreadsheets or non-secure databases is
not a good idea.
After triage, each case should be assigned to the
appropriate work channel. Each company develops