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60 Cobert’s Manual of Drug Safety and Pharmacovigilance
The Clinical Trials Information System (CTIS),
launched in January 2022, supports the flow of infor-
mation between clinical trial sponsors, European Union
(EU) Member States, European Economic Area (EEA)
countries and the European Commission.
The EMA Website
The EMA website (https://www.ema.europa.eu/en) con-
tains much useful information: Regulations, Directives,
Practices, Q&A Documents, PRAC meetings, presenta-
tions, position statements, videos and Standard Operat-
ing Procedures (SOPs). These are useful to read as there
are many of them, and they cover many areas of PV.
They give a flavor of how the EMA handles PV on an
operational level.
There is a section on European Public Assessment
Reports (EPARs), which contain summaries of product-
specific information (by brand and generic/INN name)
on the CHMP opinions in granting Marketing Autho-
rizations. There is often interesting safety information
in each document, including the SmPC and labeling as
well as the scientific reviews.
There is a very useful section on inspections for
GCP, GLP, GMP, and pharmacovigilance. The PV section
contains information on relevant documents, scope and
mission, Inspectors Working Group, and specific pro-
cedures and guidances governing inspections. The EU
Risk Management Strategies site can be found within
the EMA website.
There is an up-to-date page of links to the HAs of the
EU and elsewhere, as well as other regulatory agencies
and scientific organizations (https://www.ema.europa.
eu/en/partners-networks/eu-partners) As the EMA was
originally aimed primarily at industry and regulators,
there is less consumer information compared to the
FDA website or other national websites within the EU.
Nevertheless, more information has been added to the
website aimed at patients and the general public.
The websites of member states vary in completeness
and utility even if they are now required to maintain
clear communication and full transparency. They are
in the native language of each country, though many
have some sections in English (not always the PV sec-
tion). The website of the French HA, the Agence Natio-
nale de Sécurité du Médicament (ANSM), is useful but
is in French (http://ansm.sante.fr/). The Dutch Agen-
cy’s website (https://www.igj.nl/) has a section on PV
in English, as does the German Agency (https://www.
bfarm.de/DE/Home/home_node.html). However, many
of the key documents are in the national languages and
are not translated into English.
European Network of
Centers for Pharmaco-
epidemiology and
Pharmacovigilance
European Network of Centers for Pharmacoepide-
miology and Pharmacovigilance (ENCePP) is a net-
work of centers throughout Europe (not just the EU)
with nearly 100 centers in 21 plus countries, includ-
ing medical centers, healthcare databases, electronic
registries, and other existing networks. Their goal is
to further strengthen PV and pharmacoepidemiology
in the EU by facilitating the conduct of high quality,
multi-center, independent post-authorization studies
(PAS), both safety and efficacy (PASS or PAES), with a
focus on observational research. They have worked on
several projects, including a checklist of operational
research standards, a code of conduct, the means to
promote research in PV and pharmacoepidemiol-
ogy, an EU resources database with information on
data sources and research centers, a study database,
and the development of methodology to promote PV
research.
They are collaborating with the FDA’s Sentinel Proj-
ect and Health Canada’s Drug Safety and Effectiveness
Network.
It is also well worth subscribing to the e-mails from
the agencies as well as various blogs and news services
to stay up to date on these matters.
For more information https://www.encepp.eu/.
https://avxhm.se/blogs/hill0
The European Medicines Agency 61
Newsletters and RSS Feeds
The EMA has multiple free subscriptions available from
its website as RSS feeds https://www.ema.europa.eu/en/
news-event/rss-feeds). There are many feeds available,
and it is well worth subscribing to several of them. The
ones that may contain safety-related news are: Ongoing
public consultations, Events, Pending EC decisions and
European Public Assessment Reports (EPARs) on human
medicinal products, What’s new, Regulatory and proce-
dural guidelines, Inspections, and Scientific guidelines.
Comments
The operational issues involved in drug safety in the
EU are far more complex and numerous than those in
the US because of the multiplicity of member states and
requirements. The regulation launched in 2010–2012
dramatically improved the consistency of requirements
for post-marketing surveillance. The clinical trial PV
requirements are markedly less harmonized than the post-
marketing requirements at this writing, as specific national
requirements are still in force despite the EU regulation.
Remaining in compliance with all of the ever-changing
reporting requirements, new drug approvals, safety
issues, and such in the 27 member states plus the EMA
plus the affiliated countries presents enormous practical
and logistical problems. The EU, like the US and Japan,
is now undergoing and will continue to undergo changes
in many aspects of AE reporting (electronic report-
ing, new risk management initiatives, drug dictionary,
social media, smartphone app reporting, and “wearable”
eHealth technology, etc.). The EMA and the member
states are also becoming much more active in inspect-
ing companies’ and vendors’ drug safety practices, both
on a routine basis and on a “for cause” basis. The EU
authorities conduct PV inspections within Europe and
also abroad, which is a particularly important consider-
ation, since inspections are used as a source of income
and funding for health agencies.
In practice, what this means now is that any company
that does studies or sells (or distributes) products within
the EU must either have subsidiary or affiliated offices
within the EU (and sometimes even within each coun-
try in which they sell or study). Failing this, the com-
pany needs to engage, with a written contract, a company
(i.e., business partner or a contract research organization,
CRO) to handle these functions for it. There must be an
EU QPPV physically living and operating in the EU, and
he or she must have direct and immediate access to the
database (ICSRs, PSMF, PSURs/PBRERs, etc.) to deal
with the EMA’s and individual member states’ queries
and requests for information on marketed products. Lan-
guage issues also oblige a company to be sure it has per-
sonnel who can deal with local HAs and others in the lan-
guage of the country. The cost of doing business within
the EU to handle all the regulatory requirements is high.
Conversely, European companies wishing to do business
in the US and in Canada must also open offices in these
countries, though the US and Canada still have, to a large
degree, “one-stop shopping” at the health agencies.
We now give an example of one of the major EU
member states’ drug agencies: France. This will give
you an idea of what a large national agency may look
like and handle in the EU.
Agence Nationale de
Sécurité des Médicaments et
Produits de santé
The French Agency (today called National Agency for
Medicines Safety, ANSM) dramatically updated its orga-
nization (and name) over the past years, mainly in 2012
and 2016. As with the EMA, the principles are based
on a centralized organization with permanent ANSM
employees, supported by regional structures or experts.
The ANSM works under the care of, and is funded by
the French Ministry of Health. The website is: https://
ansm.sante.fr/. It is in French.
Missions
The main missions are assigned to the ANSM as follows:
Provide a fair access to innovation for all patients;
62 Cobert’s Manual of Drug Safety and Pharmacovigilance
Guarantee the safety of medicines throughout their
life cycle, from the first-in-human use until the
post-marketing surveillance.
Inform and exchange with other Healthcare
stakeholders
Scope
The products in the scope are drugs, blood-derived
medicines, narcotic & psychotropic agents, vaccines,
homoeopathic compounds, herbal medicines, custom-
ized preparations, biologicals (organs or tissues used as
medicines, cell- gene-therapies, blood products) medi-
cal devices (therapy, in vivo or in vitro diagnosis, medi-
cal software), cosmetics, tattoo agents, and biocides.
Even if many decisions are now taken at the EMA
level, each EU local agency can make its own decision
as long as it does not dispute the EU measures. These
measures can lead to decisions in the French public
health interest such as: Drug registration approval,
withdrawal or suspension; Clinical Trials green light;
Named patient basis use (individuals or cohort); Batch
release for vaccines or blood-derived medicines; Batch/
Product recall; Medical device ban; Import agreement;
Advertising approval or refusal.
In line with the EU regulation updated in 2010/2012,
the ANSM improved information for patients, health-
care professionals, media and increased transparency
and close collaboration with other healthcare organi-
zations (regional healthcare agencies, health insurance,
other food and healthcare agencies, scientific societies)
and patients/consumers.
Organization
A matrix organization has been set up over the past sev-
eral years as follows:
Four support departments Departments:
These are accountable for the activities and mis-
sions for:
Regulations and Ethics (including General Data
Protection Regulation)
Epidemiology and PharmacoEpidemiology
Communication & Information
Scientific Direction (transversal department enrich-
ing the scientific strategy)
Crisis & risk Management
Nine Operation Departments:
Surveillance: transversal activities in line with phar-
macovigilance, addictovigilance, biovigilance,
medical devices, surveillance during clinical
development
https://avxhm.se/blogs/hill0
The European Medicines Agency 63
External Bodies Participation: national and interna-
tional committees and boards
Registration
Medical Direction 1 and Medical Direction 2
through therapeutic areas
Med. Devices & Cosmetics
Inspections
Controls
EU & Innovation
Six Resources Departments:
Financial Audit
Human Resources
Finance and Administration
Quality Assurance, Audit and Performance
Flows and Traceability: flows mastering & Elec-
tronic Document Management Information
Systems,
The surveillance department handles pre-
registration and post-marketing surveillance with the
following missions:
Monitor signals/alerts with the support of regional
and local surveillance systems/organizations;
Ensure organization and coordination of regional
and local vigilance structures;
Monitor signals/alerts assessment and risk
management;
Enlist internal and external experts to support the
other departments in their decision-making process
in the PV field;
Maintain approval and control of advertising;
Handle a secured process for medicines supply;
Assesses the drug’s market with a medico-economic
viewpoint in a public healthcare perspective;
To support the ANSM Surveillance department, 31
regional PV centres are collecting ICSRs from hospi-
tal records or case reports provided by GPs and other
specialized healthcare professionals or patients. Based
within a hospital and university desk, they are collect-
ing case reports, informing healthcare professionals on
the drug safety profile and prescription rules. In addi-
tion, at the request of the ANSM Surveillance depart-
ment, they are involved in the safety signal detection
and assessment process, in benefit–risk assessment dos-
sier, in labeling update assessment, in PSURs/PBRERs
review and assessment; depending on their specialty/
center of interest, they also are part of various working
groups (drug–drug interaction, pregnancy, safety data-
base, etc.).
Other bodies:
The Scientific Committee:
– Ensures the scientific strategy is in line with the
latest scientific knowledge
– Is made up of ten experts nominated by the
ANSM and six by the Ministry of Health
Permanent Scientific Committees:
– Focused on specific domains of interest (cardi-
ology, dermatology, oncology, pharmacovigilance
& surveillance etc)
– Set up each for about four years, they provide
advices on specific questions
Ad hoc Scientific Committees
– Set up upon request for a specific and unantici-
pated topic / concern
Medicines Information Committee
– Consultative Committee about information and
communication for medicines
– Made up of external expert (communication,
healthcare professional, patients etc)
Liaison Committees
– Various Committees willing to maintain a good
transparency and communication with health-
care stakeholders
– Applicable for GPs, Pharmacists, patients, phar-
maceutical companies etc
Frequently Asked Questions
Q: Is it likely that the EU, the US, and the rest of the
world will “settle down” and stabilize their rules and
regulations anytime soon?
64 Cobert’s Manual of Drug Safety and Pharmacovigilance
A: Probably not. There are several factors at work. First,
the entire world of drug safety and risk management is
in a state of flux. New technology (e.g., social media,
smartphone medical apps) and regulations are being
put in place as a result of many influences, including
the following:
Consumer awareness;
Political pressures and globalization;
Economic pressures and outsourcing;
Changes in the structure of HAs (e.g., the may
expand beyond its current 27 members);
Critical safety issue(s) that have caused product
restrictions or withdrawals; and
Use of artificial intelligence sites;
Capacity limitations of governments.
The changes would be aimed at making each
member state requirements 100% consistent with
the clinical trials regulation and ICH E2A. Another
change would remove some of the ambiguity in the
causality determination requirements for SUSARs.
Currently, the investigator or sponsor makes causal-
ity determinations, though this is often difficult to
do for any particular individual case. The EU may
move toward requiring the sponsor to consult with
the investigator to determine a possible causality. If
there is disagreement between the sponsor and inves-
tigator, then the submitted SUSAR must contain both
causalities.
It is not clear that collective, global organizations
will be any more effective in drug safety as they are in
limiting arms proliferation, wars, or climate change.
Another point to note is that a decade or two ago,
the major PV players were the US, the EU, and Japan.
Since then, we have major new players gaining more
and more influence (e.g., China and India) as well as
the “discovery” of PV by most of the remaining 100
plus countries of the world on all five continents. Many
countries are putting forth PV requirements, usually in
their own languages, based largely on ICH and CIOMS
though sometimes following EU procedures more
or less. The emphasis here is on “more or less” and
regional requirements are often introduced. Many of
the new players have individual differences and quirks
in their requirements which make PV compliance in all
markets very challenging.
Q: Does one need to know any other languages
besides English if one is doing PV?
A: A delicate question. Obviously, in countries where
English is not the official language, one must know the
language of that country. Often, some documents, cover
letters, local cases, e-mails, and other requirements
must be prepared in the local language. In addition,
governmental officials, patients, healthcare workers,
and company employees are more comfortable in their
native language. Some medical terms do not translate
well language to language. Having said that, the “offi-
cial” language of drug safety is English (as much as
there can be an official language) and nearly all inter-
national documents (e.g., PSURs/PBRERs) are done in
English. However, local submission of English language
documents often requires summaries in the local lan-
guage. At a high level and on the international scene
(ICH, WHO, CIOMS), the main, or often only, business
language is English. Thus, one can often survive rather
well knowing only English, but more opportunities are
available for those with linguistic skills. As noted ear-
lier, there may be a push to use French and German as
well as other languages in the EU now that the UK left
the EU.
Q: Considering the EU regulations which will
likely continue to change in the coming years,
how can we ensure that we are up to date on the
new/latest documents?
A: Obviously, one must pay attention to changes in
requirements in all countries and markets where one
does studies or markets drugs (or has business part-
ners). There are various ways to do this depending on
the size of the organization you are working in. Within
large pharma companies, dedicated employees identify
and analyze new EMA and national documents. This
is often called “regulatory intelligence”. These people
sometimes also perform impact analyses of the new
requirements.
https://avxhm.se/blogs/hill0
The European Medicines Agency 65
At the very least, one should periodically review the
EMA website as well as other important websites (e.g.,
EudraVigilance) and the national agencies’ websites.
Small and mid-size companies may not have spe-
cific personnel devoted to such a task or to regulatory
intelligence. For these companies it may be wise to
hire a vendor that specializes in regulatory tracking.
One may also attend the periodic meetings that EMA
and some national health agencies hold to update the
pharma companies. Some private and academic organi-
zations (e.g., the Drug Safety Research Unit (DSRU) in
the UK, The DIA, also holds periodic meetings).
CHAPTER
67
6
Council for
International
Organizations
of Medical Sciences
(CIOMS)
T
his chapter summarizes the func-
tions of the Council for Interna-
tional Organizations of Medical
Sciences (CIOMS) and the reports (rel-
evant to pharmacovigilance) issued
by working groups created by CIOMS.
These reports have been crucial for
the International Council on Harmo-
nization (ICH) and the development
of safety regulations in North Amer-
ica, Europe, Japan, and elsewhere. This
chapter provides an in-depth historical
context on how CIOMS has been shaped
over the years, helping those with a
desire to understand foundational
aspects of key drug safety and phar-
macovigilance regulations. Remember
that not all proposals from the CIOMS
reports were adopted, and those were
not necessarily adopted directly and
without change by ICH and national
regulatory authorities. CIOMS cur-
rently has an observer liaison relation-
ship with ICH.
Keep in mind that unless these doc-
uments are directly put into law in a
country or region, they do not consti-
tute legal requirements.
68 Cobert’s Manual of Drug Safety and Pharmacovigilance
Introduction
From the CIOMS website (www.cioms.ch): “CIOMS is
an international, non-governmental, non-profit organi-
zation established jointly by World Health Organization
(WHO) and United Nations Educational, Scientific and
Cultural Organization (UNESCO) in 1949.” The mem-
bership of CIOMS includes 60 international member
organizations, representing many of the biomedical dis-
ciplines, national academies of sciences, and medical
research councils. No individual persons are members
of CIOMS, although individual experts serve on work-
ing groups to develop consensus reports. The remit of
CIOMS is broad, although two areas of concentration
are pharmacovigilance and biomedical ethics. The main
objectives of CIOMS are:
To facilitate and promote international activities
in biomedical sciences, especially when the par-
ticipation of several international associations and
national institutions is deemed necessary;
To maintain collaborative relations with the United
Nations and its specialized agencies, notably WHO
and UNESCO;
To serve the scientific interests of the international
biomedical community in general.
CIOMS has several long-term programs, includ-
ing one on drug development and use. Starting in the
early 1980s, working groups composed of experts from
industry and governments have been examining gnarly
issues in drug safety. They have issued many reports,
several of which have served as seminal documents for
procedures that ICH, the US Food and Drug Adminis-
tration (FDA), regulators in the European Union and
Japan, and other drug safety authorities have issued.
Key pharmacovigilance documents issued by CIOMS
working groups are summarized in the following sec-
tions. Individuals may also access the current and for-
mer working group documents by accessing the website
and subscribing to email updates.
From an operational standpoint, when a company is
developing and or reviewing their SOPs relevant to some
of the topics described within, it would be in their best
interest to download and obtain copies (often free) of
these working groups as they are working hand-in-hand
with the regulators and often have shaped the current
thinking and general practice of these topic areas.
CIOMS I (1990): International
Reporting of Adverse Drug
Reactions
The goal of this working group was “to develop an inter-
nationally acceptable reporting method whereby man-
ufacturers could report post-marketing adverse drug
reactions rapidly, efficiently, and effectively to regula-
tors”. It noted the fact that post-marketing surveillance
is necessary because pre-marketing studies in animals
and humans have “inherent limitations”. It noted the
need for standardization internationally.
The report established several conventions that
have largely been adopted, including the following:
1. The concept and format of a paper-based case
safety report (“a CIOMS I report”) from the man-
ufacturer receiving the event to the regulators.
2. “Reactions” are different from “events”. “Reac-
tions” are reports of clinical occurrences that
have been judged by a physician or healthcare
worker as having a “reasonable possibility” that
the event was caused by a drug. “Events” have
not had a causality evaluation made, and thus
may or may not be related to or associated with
the drug.
3. Causality is discussed with an emphasis on clini-
cal judgment. No method of assessing causality is
recommended. The working group recommends
that manufacturers not separate out those spon-
taneous reports that they receive (for marketed
products) into those that seem to be drug-related
and those not seemingly drug-related. The phy-
sician, by voluntarily making the report to the
manufacturer, indicates that there is some level
of causality possible in the report. This is a “sus-
pected reaction”. This has become a fundamen-
tal concept in most spontaneous reporting sys-
tems around the world, wherein all spontaneous
reports from physicians (now extended to all
healthcare providers, and in most countries, such
Council for International Organizations of Medical Sciences (CIOMS) 69
as the United States, and Canada, to consumers)
are to be considered possibly related to the drug;
that is, they are “reactions”, not “events”.
4. Because labels for marketed drugs differ from
country to country, it is recommended that all
reactions be collected at one point and then sub-
mitted to local authorities on a country-by-coun-
try basis based on whether the reactions are
labeled locally. If labeled, the reaction is consid-
ered “expected” in that jurisdiction (But see Core
Data Sheet, below, for the distinction between
“listed” and “labeled.” Note that a distinction
between these two terms is not consistently
applied.)
5. The report discusses the four minimum require-
ments for a valid report: (1) an identifiable source
(reporter), (2) a patient (even if not precisely
identified by name), (3) a suspect drug, and (4) a
suspect reaction.
6. The report recommends that all case reports be
sent in as soon as received and no later than
15 working days after receipt, to create a com-
mon worldwide deadline. This concept has
been adopted, but the 15 working days has been
changed to 15 calendar days because of differ-
ences in the designation of “working days” and
non-working days (holidays) around the world.
The reporting clock starts the date the report
is first received by anyone anywhere in the
company.
7. The CIOMS I form was created. It is essentially
the same form still used now for paper-based
exchange of case reports. This form is to be used
for reporting to regulatory authorities, unless
superseded by electronic transmission of reports.
8. Reactions are to be reported in English.
CIOMS II (1992):
International Reporting
of Periodic Drug-Safety
Update Summaries
This working group proposed a standard for Periodic
Safety Update Reports (PSURs) of reactions received by
manufacturers on marketed drugs. This standard, with
modifications from the ICH and other organizations,
has been widely adopted. The document defined sev-
eral key terms:
1. CIOMS Reportable Cases or Reports: “serious,
medically substantiated, unlabeled ADRs with
the four validity elements (reporter, patient, reac-
tion, suspect drug)”.
2. Core Data Sheet (CDS): A document prepared
by the manufacturer containing all relevant
safety information, including adverse drug reac-
tions (ADRs). This is the reference for “labeled”
and “unlabeled”. This concept, which has been
widely accepted, has since gotten more complex,
and one should distinguish labeling from listing
(e.g., unlabeled and unlisted).
3. International Birth Date (IBD): The date that the
first regulatory authority anywhere in the world
has approved a drug for marketing.
4. Data Lock-Point (Cut-Off Date): The closing
date for information to be included in a particu-
lar safety update.
5. Serious: Fatal, life-threatening, involves or pro-
longs inpatient hospitalization.
Other fundamental concepts were established:
1. Reports should be semiannual and not cumula-
tive (unless cumulative information is needed to
put a safety issue into context).
2. The same report goes to all regulatory authori-
ties on the same date irrespective of the local
(national) approval date of the drug.
3. Reactions reported should be from studies (pub-
lished and unpublished), spontaneous reports,
published case reports, cases received from reg-
ulatory authorities, and other manufacturers.
Duplicate reports should be eliminated.
4. The manufacturer should do a “concise criti-
cal analysis and opinion in English by a person
responsible for monitoring and assessing drug
safety”.
5. A sample simulated PSUR is included based on a
fake drug, “Qweasytrol”.