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200 Cobert’s Manual of Drug Safety and Pharmacovigilance
are frequently encountered that have not been seen
before. Because co-medications can play a major role
in safety reports, it is critical to know what medica-
tions (both prescription, OTC, nutraceuticals, herbal
preparations, etc.) a patient has taken. Often, however,
a strange name is encountered and much time is spent
tracking it down to understand what it is chemically. It
is far more practical to maintain a drug dictionary with
all drug names and formulations that one can refer to
as needed.
As with an AE dictionary, it is critical to enter data
in a correct and consistent fashion to retrieve it prop-
erly. Inconsistent coding produces incomplete searches
during signaling or preparing safety reports. Creating
and maintaining a drug dictionary, unlike an AE dic-
tionary, is far harder and more complex. With an AE
dictionary, the vocabulary is controlled and relatively
finite. Few “new” medical terms or diseases occur.
Many of the changes to MedDRA represent refinements
to the current terms. MedDRA is reaching, to a degree,
steady state, with changes each year in the hundreds
rather than in the thousands when MedDRA was first
released.
Drug dictionaries are quite different. New drugs are
developed almost weekly. New drugs, line extensions,
“rebranding”, new formulations, and new trade names
are developed, approved, and launched somewhere
in the world every day, and old drugs are withdrawn.
To track the names, formulations, and formulas of all
these products in more than 150 countries is an impos-
sible task. Whereas MedDRA is updated twice yearly,
a drug dictionary, if it is meant to be complete, would
need to be updated daily to weekly to remain current.
When a drug name is encountered that is not found in
the drug dictionary normally used, or if it is reported
from a country or source that is not usually seen, it is
worth doing an Internet search to verify what the drug
is or contains. Similarly, drugs that are not written in
the English alphabet (e.g., Latin, Arabic, Chinese tra-
ditional medicines, etc.) should be carefully checked.
WHO Drug Global
The most useful drug dictionary available is WHO
Drug Global, which evolved from the WHO Drug
Dictionary Enhanced and is a product of the Uppsala
Monitoring Centre (UMC). See https://who-umc.org/
whodrug/whodrug-global=. It covers 171 countries
and claims to cover nearly all of the marketed OTC
and prescription products used in these countries, as
well as many herbal remedies. This broad reach was
enabled through collaboration with IMS Health (part
of IQVIA from 2017). The UMC-IMS Health collabora-
tion dramatically expanded the WHO Drug Dictionary
into a separate dictionary type, WHO Drug Dictionary
Enhanced. Biotech and blood products, diagnostic
substances, and contrast media are also entered when
reported. See the above-mentioned UMC website for
further information.
It is required for use in clinical trials by the FDA as
of 2019. This dictionary, maintained and published on
a twice a year basis by the UMC, contained more than
620,000 unique names as of end 2023. It is updated
quarterly. It contains products registered by the FDA,
the European Medicines Agency (EMA), EU member
states, WHO member states, and elsewhere.
The “Anatomical, Therapeutic, Chemical” (ATC)
classification is used in this dictionary to categorize
active ingredients according to the body system on
which they act and their therapeutic, pharmacologic,
and chemical properties. In this classification system,
drugs are divided into five different groups and a numer-
ical code is assigned at each level of the hierarchy:
First level, anatomical main group: A — alimentary
tract and metabolism;
Second level, therapeutic subgroup: A10 — drugs
used in diabetes;
Third level, pharmacological subgroup: A10B —
oral blood glucose-lowering drugs;
Fourth level, chemical subgroup: A10BA —
biguanides;
Fifth level, chemical substance: A10BA02 —
metformin;
The coding system is complex. Basically, each
product has a unique identifier characterized by the
following:
Medicinal product name
Name specifier
Coding of Adverse Events and Drug Names 201
Drug code
Market authorization holder
Country
Pharmaceutical form
Strength available, quantity, and unit of active
ingredient.
Companies and other users have handled the dic-
tionary in various ways. Some simply subscribe to the
dictionary and use the UMC-issued updates as is. Other
companies use the WHODrug Global as a base and
add on to it as new drugs are encountered during their
regular handling of individual case safety reports each
day. This dictionary may then “grow” separately from
the official WHO dictionary into a proprietary com-
pany dictionary. This would pose reconciliation prob-
lems when the new update of the WHO dictionary is
issued, and thus some companies may choose not to
use the WHO upgrades but rather maintain their own
home-grown version. The logic behind this is reason-
able in that companies often sell limited lines of drugs
and may only rarely encounter other drugs or classes of
drugs. A company that makes primarily diabetic drugs
needs to have the latest information on all diabetic co-
medications arriving on the market but may be less
concerned about oncology and asthma drugs, for exam-
ple. They thus have their dictionary group focus on the
drugs they encounter more frequently. The downside is
that each company has a different drug dictionary and
cannot easily communicate with other companies for
licensing arrangements (or mergers) and with health
authorities, especially during electronic transmissions,
as they have different dictionaries. From the safety offi-
cer’s point of view, it is necessary to know what drug
dictionary is being used and how coding is done, espe-
cially in complicated situations and foreign cases.
EudraVigilance Medicinal
Product Dictionary
This is a product dictionary developed by the EMA for
the European Economic Area for authorized and inves-
tigational products. It has standardized terminology for
active ingredients, excipients, pharmaceutical forms,
routes of administrations, concentration ranges and
units, country codes, MAH, and Sponsor data. It is hier-
archical and multiaxial in structure and uses a standard-
ized XML schema. EU post-marketing legislation issued
in 2010 and EudraLex Volume 10 require all MAHs and
sponsors to enter into the dictionary each medicinal
product authorized in the EU or used in clinical trials.
Unlike the WHO dictionary, the EudraVigilance Medic-
inal Product Dictionary (EVMPD) uses a broader “mul-
tilingual approach” to accommodate the many Euro-
pean languages used. The EVMPD was upgraded to the
Extended EVMPD or xEVMPD. As with the EVMPD,
each MAH must populate the xEVMPD dictionary with
its approved and investigational medicinal products.
This is the so-called “Article 57 Database”. It is, thus,
an EU-centric dictionary and is used primarily by the
European Union health agencies for signaling, drug
identification, and so forth.
Future
ICH issued a document, M5, entitled Data Elements
and Standards for Drug Dictionaries in 2005. Five inter-
national standards for a new drug dictionary have been
developed by ISO called the “International Marketed
Medicinal Products” Drug Dictionary (IDMP). This is
expected to replace the xEVMPD and to be adopted
elsewhere. The xEVMPD has over 500,000 records on
medicinal products used in the EU. General Remarks
Medical coding is both a science and an art that affects
clinical outcome reports throughout the product devel-
opment life-cycle. Without a thorough understanding
of its history, origin, and purpose, we would end up
with very messy and incoherent datasets. Individuals
who are responsible for the coding of terms, medica-
tions, tests and procedures should be trained in Med-
DRA and its practices. Individuals who are responsible
for the consistency review of coding, such as medical
monitors or safety review physicians, should also be
trained and familiar with these concepts. It’s shocking
at how many individuals are tasked with the responsi-
bility to code events and yet who do not have the foun-
dational and up-to-date knowledge of the basic prin-
ciples and theory of medical coding, which is some-
thing we all wish to change. MedDRA and WHO Drug
training is widely available for free on their websites
and companies may also pay for in-person and direct
202 Cobert’s Manual of Drug Safety and Pharmacovigilance
training to their employees. The costs are relatively low
in comparison to the unrealized cost of not conduct-
ing these activities correctly the first time. Companies
should invest in this training and implement it in their
employees training requirements, else why even have
such methods and standards in the first place.
Frequently Asked Question
Q: What is your recommendation if cases
recorded in the PV database are to be updated
to use MedDRA Coding (e.g., wrong chosen
code or new MedDRA term more accurate)?
A: There is not one single possible answer to this ques-
tion, but a company policy to be defined. If the Med-
DRA codes previously chosen are inaccurate, an impact
analysis should be conducted (impacted case reports,
cases already reported to at least one HA (expedited
case reports, within aggregate reports (DSURs, PSURs/
PBRERs, PADERs), within NDA or CTD, etc.), cases
included in previous safety analysis (signal detection,
within B-R analysis reports, etc.) to determine the
extent of the changes needed. Depending on the out-
come of the impact analysis and the medical importance
of the codes to be updated, a decision would be made on
how to implement the corrective actions keep detailed
documentation.
Keep in mind that whichever dictionary(ies) are
used, they must be well integrated into the IT system
used for pharmacovigilance. Updates are expected to
be uploaded within a few weeks of their issuance and
any potential changes in old cases due to changed or
archived terms must be done rapidly. Most of the com-
mercial database systems for PV are able to do this.
CHAPTER
203
17
Spontaneous
Post-marketing
Adverse Events
W
hen a new product reaches the
market, a wider population is
exposed than in clinical trials
and spontaneous case reports play
a pivotal and irreplaceable role in
providing safety information.
Introduction
The adverse events and safety data arising from clinical
trials are only a snapshot of data within a very tightly
controlled environment. Regulations are in place that
require the ongoing evaluation and reporting of adverse
events after a product has been approved whether or not
it is then marketed (as most approved products are) or
not to ensure it continues to show efficacy and remains
safe in the public. Therefore, case reports received
after approval, otherwise known as post-marketing
reports, many of which are reported spontaneously. AEs
or ICSRs, continue to be a critical component of the
life-cycle management of the safety profile of a product.
Why is Post-Market Data
Different from Clinical Data?
Before a drug comes to market, it is studied in animals
and participants in clinical trials that aim to show the
efficacy of the product for a particular selected disease
in a highly selected sample of the population. The clini-
cal trials may be large, covering up to 10,000 patients, or
very small, covering dozens to hundreds patients (e.g.,
for orphan drugs or rare diseases). The clinical trials
also aim to define the safety profile of the drug, at least
in this selected population with this selected disease.
These studies, which are (usually) carried out
with rigorous and highly regulated methodology are
statistically powered to demonstrate efficacy, but have
204 Cobert’s Manual of Drug Safety and Pharmacovigilance
significant limitations in defining the safety profile.
They generally only find frequently occurring adverse
events (AEs). For example, if in studying 10,000
patients not a single patient has a particular AE, such
as a heart attack, we can be only 95% confident that the
chance of having a heart attack based on the data from
this trial is less than 1 in 3,333 (per the Rule of Three).
If we raise the safety threshold to be 99% confident that
a heart attack has an incidence of only 1 in 10,000 with
this drug, we would need to have no heart attacks in
46,000 patients studied. In other words, studying even
5,000 or 10,000 patients does not give enough evidence
that the major or rare safety issues have been identi-
fied before the drug goes on the market for large-scale
use in patients with a wide range of disease severity, co-
morbidities or co-medications, etc.
This means that the uncommon AEs and even the
fairly common AEs (e.g., an incidence of 1 in 500) may
not be identified until the drug is extensively used in the
general population after marketing. When, say, a million
people start using a new drug in the months after a prod-
uct launch, a “rare” AE with a 1 in 10,000 incidence rate
could be expected in about 100 patients. Should the AE
in question be dramatic and rapidly discovered, such as
torsades de pointes, aplastic anemia, or rhabdomyolysis
(a severe skeletal muscle injury), there will be a torrent
of recriminations about why this was not discovered ear-
lier during the clinical testing. The correct response is
that the testing of only 5,000 to 10,000 patients could
not pick up such a rare event because this is the way the
drug approval system is designed.
Also, of note is that clinical trials are often done in
a narrow group of patients. For example, an antihista-
mine may be tested in otherwise healthy adults between
18 and 60 years of age with allergies. Even if the drug
is only approved for use in this population, physicians
in most jurisdictions have the right (which they freely
exercise) to prescribe the drug for anyone and for any
disease. Thus, many people with other diseases and at
the extremes of the age range (the very old and young)
receive the drug and may have AEs that the healthy 18-
to 60-year-old study population did not experience in
the clinical trials. The elderly, for example, are partic-
ularly sensitive to certain AEs (e.g., swallowing disor-
ders) or to certain classes of psychotropic drugs and
they often are taking multiple medications.
Polypharmacy and drug interactions, among other
things, cannot be adequately studied in the preapproval
setting. Although food interaction studies and some
drug interaction studies are done before approval, it
is not possible to study “real world” patients (often
elderly) who take many drugs and have peculiar or
irregular eating and drinking habits. Even after market-
ing, it is difficult or even impossible to predict or know
how the use of three, four, or more drugs given at the
same time will act or interact.
Hence, particular attention must be paid to the time
just after a product is first marketed to fully understand
the drug’s safety profile and minimize risks. In a sense,
the first 500,000 to 1,000,000 patients who are pre-
scribed the drug after launch are doing the large-scale
safety testing. And, outside of clinical trials, the report-
ing of safety information by healthcare practitioners
and other members of the public to manufacturers and
drug regulators is nearly always voluntary.
What this means then is that the entire edifice of
the drug safety system as it now stands, depends on the
good will and energy of nurses, pharmacists, physicians,
dentists, and consumers to report AEs. Without them,
no one would know of the AEs that are appearing as
individual cases in isolated areas around the country or
the world. These people must take time out of their day
to report such events. The report will inevitably lead
to a request for supplementary data (laboratory reports,
cardiograms, hospital records, etc.) that are time- and
effort-consuming. There is no evident or immediate
gain to the reporter. The gain rather is to society at
large, which is largely unaware of this noble effort.
Health authorities and regulators well understand
the weakness of this system. Major efforts are now
under way to look at how the spontaneous reporting
system has worked in the past. That is, although we
think it is useful and appropriate to rely on this system,
did it, in fact, lead to early pick-up of serious problems,
leading to a change in the product labeling and its use
in clinical practice?
Various health agencies, particularly in North Amer-
ica and Europe, are looking at this question and novel
approaches to supplement the existing system.
There is a lot more digital data, sitting in the cloud,
on drug safety that is not being looked at in a systematic
Spontaneous Post-marketing Adverse Events 205
manner. Obtaining these data on an ongoing basis and
using them for safety analysis is an obvious way to iden-
tify a drug’s safety profile. However, the devil is in the
details. The databases around the world must be identi-
fied and the data extracted in a valid and consistent way.
This is a very difficult task since data collection is not
yet standardized and there is little true interoperabil-
ity across IT systems. It is also important to remember
that safety generally represents a secondary use of these
datasets. Multiple efforts (both nationally and glob-
ally) are under way to standardize and normalize data
so that they are easily collected, databased, retrieved,
and analyzed in a useful, valid, and rapid manner. If
every encounter a patient has with the healthcare sys-
tem is digitalized, we should be able to retrieve excel-
lent safety data rapidly. This, however, will take years
to achieve on a national level, let alone a global level.
When this does occur, the spontaneous reporting sys-
tem may then decrease in importance. The fundamen-
tal system now in place to discover AEs with marketed
products remains the spontaneous reporting system.
This system is used, in one form or another, in many
countries around the world; examples include the US,
Canada, China, the EU, Japan, South Korea, Australia,
New Zealand, South Africa, and many other countries
around the world. The WHO and the Uppsala Monitor-
ing Centre actively work with more than 150 countries
to set up pharmacovigilance (PV) systems and increase
capacity.
The principles of the Spontaneous Reporting Sys-
tem (SRS) are simple. All healthcare professionals (and
consumers in most countries, including the US, the EU,
and Canada) are encouraged (and sometimes required
by post-marketing requirement, such as US REMS or
registry studies) to spontaneously report AEs to either
the manufacturer or the governmental healthcare
agency or a third party. Standardized forms have been
developed (the MedWatch form in the United States,
the CIOMS I form elsewhere) specifically for this pur-
pose and are available online, in publications (e.g., the
Physicians’ Desk Reference in the United States), as apps
on the iPhone and other smartphones, and elsewhere.
The form can be folded up and mailed (postage-free),
faxed, or filled in online and uploaded to the healthcare
agencies. Phone, on-line reports and faxes to the man-
ufacturer and most health agencies are also possible.
However, many jurisdictions require companies to
use an electronic format (viz. E2B) to transmit safety
reports to regulators
In the US, the United Kingdom, and other coun-
tries, information submitted spontaneously to the
health authority is available for free or for a small fee
to anyone in the public under Freedom of Informa-
tion Acts. The cases are redacted before being released
by the health agency to avoid identifying the patient
or reporter In the US, in 2022 over 76.000 individual
reports were sent directly to FDA (3%) with the remain-
ing 2.3 million sent to the manufacturers who then for-
warded these cases to the FDA. Redacted case report
data held by FDA in the FAERS database are publicly
available over the Internet by using an FDA-supplied
public dashboard. Google FAERS public dashboard to
examine the data yourself. In 2022, the breakdown of
the sources of reports was equally divided by health care
professionals and consumers.
Timelines for
Post-Marketing Reporting
The requirements for AE reporting have largely been
standardized through the International Council for
Harmonization (ICH). Reporting for healthcare pro-
fessionals (and consumers in most places) is usually
voluntary and is highly encouraged by regulatory agen-
cies, although there is some skepticism about the utility
and value of consumer reports, particularly those for
OTC products and those not validated by a healthcare
professional.
There is no time frame for reporting by a consumer
or healthcare professional after the occurrence of the
AE, but obviously rapid reporting is preferred for pub-
lic health reasons; in some cases, it may save lives. For
manufacturers, reporting is obligatory in almost all juris-
dictions, and typically within a 15-day (calendar) time-
frame, although there are slight differences depending
on the region and type of event (domestic or foreign).
Any AE that comes into a company, whether through
sales representatives, phone calls, Internet and e-mail,
literature reports (which must be actively searched for
by the company), patient support programs, or other
206 Cobert’s Manual of Drug Safety and Pharmacovigilance
media must be rapidly forwarded to the Drug Safety
Unit and reviewed by qualified medical personnel.
For marketed drugs in most countries, all serious
AEs that are unexpected (i.e., that do not appear in
the regulator-approved product labeling) and possi-
bly related must be reported to the health author-
ity by the company within 15 calendar days. In the US,
most of the remaining serious and non-serious cases
must be reported to the FDA in NDA periodic reports
(PADERs) or PSURs/PBRERs (quarterly for newer drugs
and yearly for older drugs). In some countries aggregate
periodic reporting is done as PSURs/PBRERs, which are
prepared according to a schedule, depending on the age
of the drug and the country receiving the report. In the
EU, PSURs (in PBRER format) periodicity is established
by regulators. A regulator may also request a periodic
report at any time.
These reports contain line listings of various cuts
of the data as well as medical analyses prepared by the
company’s medical team, usually headed by a physician.
They look at AEs that are expected and unexpected and
indicate which need to be added to the drug labeling
as new ADRs, warnings, precautions, and so forth, and
which AEs/ADRs need to be watched with heightened
vigilance. These reports are then scrutinized by the reg-
ulatory agencies who may agree or disagree with the
company analysis and who decide on changes to the
drug labeling, conditions of marketing of the drug, and
so forth. There is usually dialogue between the health
agency and the company before an action is taken,
though health authorities are empowered to act imme-
diately and unilaterally if the public health is at risk.
At the health agency, the data are then entered into a
database and reviewed. Analysis of individual AE cases
and of aggregates of AE cases is done.
Specifically, regarding spontaneous reports, a com-
pany must set up a failure-proof system to receive, pro-
cess, report, and analyze AEs. Time is of the essence,
because some of the reports must be sent to the health
authorities within 15 days. The clock for reporting
starts counting down from the moment the first person
anywhere in the company (or a partner, co-marketer,
etc.) learns about a “valid” AE. This is Day Zero for the
report.
Sources of Spontaneous AEs
Once a product has been marketed, safety information
can be received via a variety of different means and
sources, each one needing its own process and pro-
cedure to ensure accurate and timely communication
of the information. After marketing, a company can
receive safety data via:
Phone, fax, email, mail
Websites and web forms (with open text fields)
Social Media accounts (any account that can receive
a message from the public, such as LinkedIn, Face-
book, Instagram, X, etc.)
Sales Representatives, Medical Science Liaison (any
company representative having direct engagement
with healthcare professionals)
Marketing firms
Medical Affairs teams and Medical Information Call
Centers (MICC)
Customer Service representatives
Administrative positions, such as front office staff
Lawsuits
For phone reports, this means that any phone
number in the company is a potential source
of AE reports, and anyone who answers the phone
in the company must be instructed what to do if an
AE report comes into a place where it is not normally
expected. A rapid and painless (to the caller) transfer
system must be set up if the information is not imme-
diately written down by the company employee first
answering the call. No one wants to be kept on hold or
to repeat the same story for the third or fourth time. It
is not acceptable to lose even one AE, so The call must
be handled properly. Because some AEs may need to be
reported to one or more healthcare agencies within 15
days, time cannot be lost. The company must be ready
to accept calls 24 hours a day, 7 days a week (includ-
ing holidays) and in multiple languages if that is the
normal custom in the country. Many companies do not
maintain 24-hour coverage in their company, prefer-
ring to outsource this function to private companies
(sometimes abroad, often in India or Costa Rica). Many
companies, even those maintaining a call center during
Spontaneous Post-marketing Adverse Events 207
business hours, outsource after-hours calls to poison
control centers or private companies. Many companies
also use this number (e.g., a toll-free number) for other
functions, including product information, queries, and
marketing.
Similarly, any e-mail or website or social media
site in which an outsider can send a message or key
in free text is a potential source of AEs. Many compa-
nies, much to their chagrin, receive complaints and AEs
on job-posting websites, free sample websites, survey
websites, smartphone apps, customer engagement pro-
grams, and so forth.
Sales representatives must also be aware that a
physician, pharmacist, or other healthcare worker
they call on may be the source of an AE. Even innoc-
uous off-the-cuff remarks about a possible AE (“Oh,
by the way one of my patients took your other drug
XXXX and had a heart attack the next day”) made
to a company representative constitute a report to
the company that must be acted on. Even offhand
remarks over the barbecue on a Sunday afternoon
in which a neighbor casually relates an AE to a com-
pany employee must be reported to the drug safety
department! Some pharma companies include a spe-
cific sentence in the employees contract which speci-
fies that, should he/she be informed of an ADR with a
company’s drug, he/she must report this information
to the drug safety department within a certain time-
frame. Most companies also have this noted in their
SOPs and training materials. Many companies require
annual training (with documentation of successful
and timely completion).
Some companies have media services that review
transcripts of newspapers, television shows, websites,
blogs, and so forth, looking for anything about their
products. Should AEs be noted, they must be sent to
the safety department. There is no obligation to scan
the web trawling for AEs, but anything found on a com-
pany-sponsored website or merely discovered in the
course of surfing is a reportable AE.
Lawsuits often represent the point of entry of AEs.
The legal department must be aware that they must also
report the AE noted in the suit to the safety department
usually within 48 hours.
Some people still write “snail mail” letters, and the
company mail room or mail screeners must be aware
that AEs received in the mail are to be sent to the drug
safety group immediately (usually by PDF/e-mail or fax
and not interoffice mail).
One of the more complex problems companies face
is the phone call or letter that notes a product com-
plaint (“the pill was the wrong color”), an AE (“and
then I took it and had violent stomach pains”), and then
requests restitution (“I want my money back now!”).
These cases must be handled by three or more depart-
ments in the company: (1) the drug safety group to get
details and report the AE, (2) the manufacturing or
quality group to see why the pill was the wrong color,
and (3) the marketing/sales group to refund (or not
refund) the money. Companies must set up systems to
handle this.
United States Regulations
The United States reporting requirements for sponta-
neous reporting are found in 21CFR314.80. Serious,
unlabeled (US Package Insert), spontaneous, and liter-
ature events, whether felt to be causally related or not,
must be reported within 15 calendar days (plus day
0) when the four minimum validity criteria are met.
Reports from FDA, either from the MedWatch to Manu-
facturer Program or FOI, do not have to be sent to FDA
but may need to be sent to other HAs.
European Union
Requirements
The EU regulations are far more complex in terms of
sponsor and applicant reporting. Some go to the health
authority at the national or provincial level and some
go to a non-health-authority-designated agency. All
cases should go to EudraVigilance. Reporting depends
on whether the case comes from an EU Member State
or from outside the European Union. See the exten-
sive descriptions in Good Pharmacovigilance Prac-
tice (GVP) module VI (Collection, management and
208 Cobert’s Manual of Drug Safety and Pharmacovigilance
submission of reports of suspected adverse reactions to
medicinal products) at the EMA website (Google EMA
Good pharmacovigilance practices).
The GVP modules are updated from time to time;
local updates from Member States should also be
tracked in case of changes in the requirements.
Other Regions
Many countries follow the ICH/CIOMS criteria for
reporting valid cases (four criteria: suspect drug, AE,
patient, reporter) from spontaneous sources. It is import-
ant to triage every case immediately. If it is a serious
AE and unlabeled, most jurisdictions require reporting
to the health authority within 15 calendar days of first
awareness. Some countries have different requirements
which often revolve around receiving all domestic SAEs
(whether labeled or not) but only some (SAEs that are
unlabeled) non-domestic cases. Some countries do not
want any non-domestic cases. Some non-English speak-
ing countries require cases to be in the local language,
particularly domestic cases.
Australia: Interestingly, Australia only requires
Australian SAEs to be reported within 15 calendar days,
whether expected or not, using their “blue card” system
(the official Australian system to capture AEs is akin to
the US MedWatch program and the United Kingdom
Yellow Card system) as of this writing. In addition to
the “blue card” reporting form (electronic web-form
and on paper), the Therapeutic Goods Administration
(TGA) accepts E2B ICSRs. Non-serious Australian AEs
should be reported as line listings in the PSUR. For post-
marketing studies done in Australia, similarly, all SAEs
are to be reported in 15 calendar days and the non-serious
AEs at the end of the study. Non-Australian cases do not
have to be reported. Rather “any significant safety issue
or action which has arisen from any analysis of foreign
reports, or which has been taken by a foreign regulatory
agency, including the basis for such action” should be
reported to the health authority (TGA) within 72 hours
(www.tga.gov.au).
Canada: Health Canada requires all domestic
reports of serious ARs and “unusual failure in efficacy
for new drugs” be reported within 15 calendar days.
Foreign unexpected serious adverse reactions must be
reported in 15 calendar days.
There is now a transition by companies reporting
serious AEs to health agencies from paper or fax report-
ing of paper forms (CIOMS I) to electronic reporting
using a standardized electronic format and transmission
known generically as “E2B transmissions” after the ICH
document of that name. This reporting is either through
the Internet (using an electronic gateway or direct entry
online into the database). In theory, electronic case
transmission of a case is the same to all agencies around
the world and simplifies the multiple reporting obliga-
tions now in force from country to country. This has not
turned out to be entirely the case, however, as various
countries (notably the US, Japan, and China) want spe-
cial or additional information and data in the electronic
transmission. Further, the EMA has created a new paper
form for output of E2B(R3) ICSRs. Note that most of
the local customization relates to administrative detail
and not the medical case.
Process Issues
There is also a trend toward reporting from standard-
ized lists of drug names, medical and surgical history,
AE codes, laboratory data, and demographic codes.
This allows people to document AE cases in a standard-
ized language and format that is easily translated by
the computer into any other language. The only area
proving resistant to this computerization is the medi-
cal narrative, where a case is summarized in prose in a
few paragraphs such that the reader can get an under-
standing of what happened to the patient. Whether a
computer-derived narrative (or no narrative at all) will
prove to be as useful as a narrative prepared by a safe-
ty-trained healthcare professional remains to be seen.
Harnessing artificial intelligence and machine learning
may facilitate this.
Interestingly, English has become the international
language of AE reporting for most countries. PSURs
and E2B transmissions are written in English. Some
countries require translation of some or all sections,
Spontaneous Post-marketing Adverse Events 209
but this is becoming less prevalent as short time
frames and international harmonization are requiring
that English be the language of drug safety — at least
for 15-day expedited reporting and periodic report-
ing. Sometimes AEs occurring in a particular country
must be reported to the national health authority in
the language of that country rather than or in addition
to English.
After the report is received or uploaded to the data-
base in a company’s safety department, it must be logged
in and a unique number assigned (either before or after
a search for duplicate cases). How this is done depends
on whether the case arrives electronically or has to
be manually entered into the safety database. A rapid
determination must be made by a medical professional
to see whether it is an “expedited” or “alert” report that
must be sent to the health authorities within 15 calen-
dar days of first arrival. The data must be entered into
the database (if not already uploaded), coded, medically
reviewed, quality-checked, and dispatched outside the
company to the appropriate health authorities, subsid-
iaries, and business partners, as well as to others inside
the company such as clinical research physicians who
follow the safety profile of the drug in question. Any
horrific AEs that might produce immediate regulatory
or public health problems must also be identified and
acted on urgently.
From a more general point of view, the wisdom
of relying on spontaneous reporting of AEs, and thus
trusting the goodwill and timely reporting of the health-
care community and patients, has been seriously ques-
tioned in the past few years. As several drugs have been
withdrawn from the market or have had urgent labeling
changes made following the reports of severe toxicity,
the search for a more efficient method of rapidly identi-
fying new safety issues is under way in many quarters.
The FDA and EU continue to examine its spontaneous
reporting system for efficiency and other health agen-
cies around the world are also examining better mecha-
nisms to capture SAEs.
It is highly likely that electronic healthcare records
will in time supplant the spontaneous AE reporting
systems now in place. With the electronic tracking
of all patients’ encounters with the healthcare system
(prescriptions given and filled, doctor visits, hospi-
tal stays, complaints and diagnoses recorded in stan-
dardized forms, etc.), it is likely that health agencies
and possibly companies will be able to “mine” the
information using complex search algorithms and
artificial intelligence tools to do real-time SAE track-
ing. Prospective use and epidemiology studies will
become feasible. Adding genomic data, health eco-
nomic information, and other data will transform the
drug safety surveillance system. This is not likely to
happen soon and there will surely be false starts and
dead ends in the quest to obtain drug safety data, but
there is little doubt that this will occur to everyone’s
(presumed) benefit. Note also that the regulations
for the handling and reporting of post-marketing
AEs are not static in spite of “harmonization”.
Frequently Asked Questions
Q: Is it really worthwhile reporting another
penicillin rash or some other clearly well-de-
scribed adverse event? Isn’t this a waste of
time, money, and resources that could be bet-
ter used elsewhere?
A: Yes, that is probably true. Known reactions for old
drugs in the approved patient populations using the
approved formulation, dose, and route of administra-
tion do not really add much to the general knowledge of
drug safety. It probably is better to use limited resources
looking at newer drugs or patient groups where safety is
less well characterized.
This is not what most health agencies (officially)
say for the understandable reason that, once they ask
healthcare professionals and consumers to start making
judgments about what is worth reporting and what is
not, they begin the slide down the slippery slope. Their
reasoning is that it is better to over report, even known
AEs on old drugs, than under report and risk missing
something. After many years on the market, even old
drugs can have new data found on AEs and in partic-
ular drug interactions. Whether enough resources will
remain available for this remains to be seen. Regardless,
companies must follow the regulations, regardless of the