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6 Principles ofPharmacovigilance andDrug Regulation
141
Table 6.1 (continued)
Legislation Contents
Directive 87/22/EEC [51] Concertation procedure for high-technology drugs
– Mandatory for drugs developed through biotechnological processes and
optional for other innovative drugs
– Required when an MA in more than one member state is sought
– Assessment by the CPMP, though opinions not binding
Directive 88/320/EEC [52] Verication and inspection of good laboratory practice
Directive 89/341/EEC [53] Package leaet and good manufacturing practice
– Requirement for a package leaet
– Requirement to comply with good manufacturing practice
Directive 91/507/EEC [54] Update of quality, pre-clinical and clinical data requirements
d
– Adaptation to state-of-the-art science
– First mention of “benet/risk” assessment and prole, including to monitor it
post-authorisation
– Third condition for MA in exceptional circumstancesf: post-authorisation
studies
g
e
Directive 93/39/EEC [55] Mutual recognition, pharmacovigilance, and post-authorisation
– Replacement of the multistate procedure with the mutual-recognition
procedure, with CPMP opinions now binding
– Need to establish national pharmacovigilance systems
– Requirements for pharmacovigilance for national MAs, including a qualied
person and (periodic) reporting of adverse reactions
– First mention of “specic obligations” in the context of MA in exceptional
circumstancesf, including post-authorisation studies and notication of adverse
reactions
– Recognition of potential environmental risks of drugs
Regulation (EEC) No 2309/93
[56]
EMEA and the centralised procedure
– Establishment of the EMEA:
h
• To house and support the CPMP
• To coordinate pharmacovigilance
• To coordinate good laboratory, manufacturing, and clinical practice oversight
– Replacement of the concertation procedure with the centralised procedure,
with binding CPMP opinions
– Annual review of specic obligations for MAs in exceptional circumstances
– Requirements for pharmacovigilance for MAs through the centralised
procedure, including a qualied person and (periodic) reporting of adverse
reactions
– Need for an environmental risk assessment
Regulation (EC) No 540/95
[57]
Non-serious, unexpected adverse reactions
– Detailed requirements for periodic reporting
– Specication of conditions requiring variation of MA
CPMP Committee for Proprietary Medicinal Products, EEC European Economic Community, EU European Union,
EMEA European Agency for the Evaluation of Medicinal Products, MA marketing authorisation, SmPC Summary of
Product Characteristics
a
Later known as “Authorisation under Exceptional Circumstances”
b
Not applicable to immunological drugs, radiopharmaceuticals, drugs derived from human blood or human plasma, and
homeopathic products, for which separate directives were later issued
c
For drugs that are “essentially similar” to already authorised drugs (later known as “informed consent” and “generic”
applications) and drugs of which the constituents have a “well-established medicinal use”
d
Now including immunological drugs, radiopharmaceuticals, and drugs derived from human blood or human plasma
e
“… in order to monitor the benet/risk assessment after marketing authorisation has been granted, any change to the
data in the dossier, any new information not in the original application and all pharmacovigilance reports, shall be submitted to the competent authorities”
f
See Directive 75/318/EEC
g
“… an identied programme of studies within a time period specied by the competent authority, the results of which
shall form the basis of a reassessment of the benet/risk prole”
h
Initially mandatory for certain biological drugs and optional for other innovative drugs
142
L. T. Bloem et al.
for Proprietary Medicinal Products (CPMP)—
instated in 1975—would guide these procedures
and act as arbitrator when member states disagreed about safety issues, or as primary assessor when it concerned innovative drugs such as
in the concertation and centralised procedures.
However, its opinions were not always binding
and required regulatory action by the EC or regulatory agencies in individual Member States.
While Table6.1 lists many important developments that contributed to the EU regulatory harmonisation process, one important regulatory
development should be discussed here. In 1983,
companies were required to provide a Summary
of Product Characteristics (SmPC) together with
their application for a marketing authorisation, to
be assessed and agreed by the regulatory authorities. This should facilitate the exchange of information between member states [48]. Shortly
thereafter, the CPMP published an SmPC guideline that outlined a specic order of information
in the SmPCto optimise its relevance as an information source for healthcare professionals [58,
59]. Moreover, legislation about the advertising
of drugs to healthcare professionals required that
this should be done in line with the SmPC [60].
Thus, the SmPC became an important regulatory
means to communicate information about the
safe and effective use of drugs to healthcare
professionals.
The CPMP considered matters of pharmacovigilance since its inception in 1975 and was
supported for this purpose by the
Pharmacovigilance Working Party (PhVWP)
from 1989 onwards. Their activities comprised
for example the establishment of a safety communication system, the organisation of pharmacovigilance hearings, and the incorporation of
safety information in the SmPC [61].
The process of regulatory harmonisation in the
EEC culminated in 1995 when, following the
establishment of the European Single Market and
the EU in 1993 [44], the EMEA was established.
Along with the EMEA, a “centralised procedure”
for regulation of innovative drugs was established
[56], and a “mutual recognition procedure” to
ensure harmonisation of regulatory decisionmaking for other drugs [55]. The opinions of the
EMEA’s main scientic committee, the CPMP,
were now binding for all member states. Moreover,
pharmacovigilance activities were specied in
legislation, including immediate reporting of serious adverse events by companies to the regulatory
authorities, and the periodic reporting of all newly
available data on adverse events with a scientic
evaluation of a potential causal relationship (later
known as periodic safety update reports or
PSURs) [55–57]. Later, in 2004, the names
EMEA and CPMP were changed to EMA and
Committee for Medicinal Products for Human
Use (CHMP) [62].
2.5 The Drug Regulatory
Response totheHIV/AIDS
Epidemic
In response to erce activism for increased availability of and access to drugs to treat HIV/AIDS,
the Accelerated Approval pathway for marketing
authorisation was introduced in the US in the
early 1990s. Together with other regulatory pathways, it enabled the FDA to accept preauthorisation evidence from fewer trials or based
on surrogate rather than clinical endpoints. The
benet–risk balance should then be conrmed by
additional evidence from post-authorisation studies. These pathways were aimed at drugs for lifethreatening diseases, including HIV/AIDS, and
explicitly considered severity of disease and
availability of alternative treatments in the benet–risk assessments [63]. In Europe, a similar
regulatory pathway had been available since
1975, for which it was possible to request post-
6 Principles ofPharmacovigilance andDrug Regulation
Table 6.2 Selection of drugs withdrawn for safety reasons
Year Active substance Type of drug Type of adverse events
2004 Rofecoxib Analgesic Cardiovascular
2008 Lumiracoxib Analgesic Hepatic
2009 Rimonabant Anorectic Psychiatric
2010 Benuorex Anorectic Cardiac
2010 Rosiglitazone Antidiabetic Cardiac
2010 Sibutramine Anorectic Cardiovascular
2010 Sitaxentan Antihypertensive Hepatic
2012 Buomedil Vasodilator Cardiac, neurological
2012 Meprobamate Sedative Neurological, psychiatric
2013 Nicotinic acid/laropiprant Hypolipidaemic Bleeding, myopathy, infections, diabetes
2016 Fusafungine Antibiotic Allergic
2017 Gadodiamide, gadopentetic acid,
gadoversetamide
2018 Flupirtine Analgesic Hepatic
2018 Daclizumab beta Immunosuppressant Immune-related
2019 Cinoxacin, umequine, nalidixic acid,
pipemidic acid
2020 Ingenol mebutate Chemotherapeutic
Selected from European Medicines Agency [66–69], Lane etal. [70], McNaughton etal. [71], Onakpoya etal. [72],
World Health Organization [73]
Gadolinium contrast
agents
Antibiotics Involving tendons, muscles, or joints;
(topical)
Brain deposition
neurological; psychiatric
Skin cancer
143
authorisation studies as of the early 1990s: the
Authorisation under Exceptional Circumstances
[46]. This pathway too was used to authorise several drugs to treat HIV/AIDS.
2.6 Global Harmonisation
Many of the early EEC evidence requirements
contributed to worldwide evidentiary standards
through the International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH). By 1990, the ICH formed an international
platform for regulatory authorities and the pharmaceutical industries of Europe, Japan, and the
US to formulate guidelines and technical requirements [64]. Further international collaboration
between regulatory authorities was effectuated
when the International Coalition of Medicines
Regulatory Authorities (ICMRA) was established in 2012, an informal group of leaders of
global regulatory authorities [65].
2.7 Safety Withdrawals
Despite efforts throughout the more recent history of drug regulation, safety issues have continued to occur, some of which required
complete withdrawal from the market
(Table6.2). Therefore, more proactive pharmacovigilance has gradually been developed [74],
which is discussed in Sect. 3.
3 Current Principles
ofPharmacovigilance
andRelated Aspects inDrug
Regulatory Decision-Making
This section discusses in detail the principles and
important aspects of contemporary pharmacovigilance as well as related aspects in drug regulatory decision-making. As highlighted before,
these aspects are the result of international developments over decades. Therefore, before diving
into these principles and aspects one by one, rst
144
L. T. Bloem et al.
the most important developments concerning
pharmacovigilance in the twenty-rst century are
reviewed.
3.1 Pharmacovigilance
intheTwenty-First Century
Leading up to the twenty-rst century, specically in the EU, more and more pharmacovigilance procedures were introduced. Important
milestones were the establishment of the
Pharmacovigilance Working Party (PhVWP) in
1989 [61], which was instigated to support the
CPMP—later CHMP—on post-authorisation
safety issues. In 1993, the reporting of adverse
events was harmonised, including the requirement for a PSUR (see Table6.1), and in 2001, the
EudraVigilance database of suspected adverse
reactions became operational [75].
In 2005, the EU Risk Management Plan
(RMP) became mandatory for drugs containing a
new active substance and regulators could
requireaPASS as a condition to the marketing
authorisation [62, 76, 77]. When the current EU
pharmacovigilance legislation came into force in
2012, pharmacovigilance was strengthened with
a central role for the EMA’s new
Pharmacovigilance Risk Assessment Committee
(PRAC) that replaced the PhVWP to advise the
CHMP on all matters of pharmacovigilance and
risk management [78].
Further strengthening of pharmacovigilance
was achieved by expanding existing requirements, introducing new ones, establishing new
procedures, and developing new pharmacovigilance tools. Requirements for reporting of suspected adverse reactions to EudraVigilance
were extended to include all suspected adverse
reactions that occur within the EEAand serious
adverse reactions outside it. The denition of an
adverse reaction was expanded to also include
medication errors and effects of off-label use.
The submission of an RMP became mandatory
for all drugs, the content and focus of the PSUR
was revised, and PSURs of drugs authorised in
more than one EU member state were now all
assessed at the European level through a PSUR
single assessment procedure (PSUSA) with a
binding outcome for all drugs with the same
active substance. For signal detection, a central
role was given to EudraVigilance and the PRAC
for prioritisation and assessment of signals,
leading to a recommendation that is applicable
to all affected drugs authorised in the EU [78–
80]. The EU pharmaceutical legislation was
accompanied with a set of guidelines on Good
Pharmacovigilance Practice (GVP) that describe
structures and processes of all pharmacovigilance tools and procedures, but also how the EU
network operates [81].
3.2 Pharmacovigilance
Throughout theDrug
Lifecycle
While the decision to allow a new drug to be marketed in short is the answer to the question as to
whether there is evidence to demonstrate that the
drug’s benets outweigh the anticipated risks, the
evaluation of the drug does not end once marketing is granted. The drug’s benet–risk balance
continues to be monitored throughout the entire
lifecycle of the product. This is needed since at
the time of initial authorisation, the knowledge
about benets and risks is usually based on results
from clinical trials, as well as data from animal
studies. As the clinical trials are relatively short
and include relatively few subjects compared to
the number of patients that will be exposed to the
product once it is placed on the market, these
studies are unable to provide information on the
occurrence of delayed and uncommon or rare
adverse reactions. Moreover, subjects in clinical
trials tend to be selected from a more homogeneous and healthier population with fewer comorbidities and less complex disease than the patients
that will be exposed in the post- marketing setting
and information on relevant subpopulations such
as children, elderly, or pregnant women may be
lacking at the time of authorisation.
The monitoring of the benet–risk balance
throughout the lifecycle of a drug is mostly
focused on safety, i.e. pharmacovigilance,
although for some newly authorised drugs,
6 Principles ofPharmacovigilance andDrug Regulation
145
regulators require further conrmation or demonstration of the product’s efcacy (see Sects. 3.7
and 3.8 below). Pharmacovigilance aims at preventing harm from adverse reactions in humans
arising from the use of authorised medicinal
products and promoting the safe and effective use
of medicinal products, in particular through providing timely information about the safety of
medicinal products to patients, healthcare professionals, and the public [82]. In practice, pharmacovigilance is operationalised with a range of
activities such as signal detection, periodic safety
reporting, and risk management planning.
3.3 Risk Management Planning
The concept of the EU RMP was devised in 2005
[62, 76, 77]. Since then, both the requirements to
the content of the RMP and the situations in
which an RMP is required have been revised several times. The RMP enables regulators to proactively monitor and address safety issues
throughout the drug’s lifecycle by identifying,
characterising, and minimising drug’s important
risks. To achieve this goal, the RMP consists of
three main elements. The rst part is called the
“safety specication” and describes the drug’s
important identied risks, important potential
risks, and missing information. The second part,
the “pharmacovigilance plan”, describes the
pharmacovigilance activities that are needed to
further characterise the risks and missing information in the safety specication. For important
adverse events for which a causal relationship
with the drug has been established, the characterisation would comprise a better understanding
of risk factors, severity, or frequency of the
adverse reaction, while for the important potential risks this would constitute conrming or
refuting of the relations between the adverse
events and the drug. The last main part of the
RMP provides details of the “risk minimisation
measures” that will be taken to reduce the risks
associated with respective safety concerns. These
measures comprise routine risk minimisation
measures, such as the product information, and
additional risk minimisation measures, such as
educational tools for healthcare professionals and
patients, Direct Healthcare Professional
Communications (DHPC) or “Dear Doctor” letters, and pregnancy prevention programmes [83].
See the case study on valproate (Case study 1)for
some examples.
Internationally, ICH released its
Pharmacovigilance Planning E2E Guideline in
2004 [84] and provided a basis for the EU RMP.
The ICH E2E Guideline dened two parts of the
RMP: the safety specication and the pharmacovigilance plan (not the risk minimisation measures).
With this ICH Guideline, the concept of an RMP
has also been adopted in other regions worldwide,
under different names such as the Risk Evaluation
and Mitigation Strategy (REMS) in the US.This
REMS also includes specic plans to mitigate
known risks, but not the pharmacovigilance activities as in the EU RMP [85]. The Canadian RMP
essentially requires the same elements as the EU
RMP [86], and the Australian regulator Therapeutic
Goods Administration (TGA) requires an EU RMP
with an Australia-specic annex [87].
3.4 Pharmacovigilance Activities
For regulatory purposes, pharmacovigilance
activities can be divided into routine pharmacovigilance activities and additional pharmacovigilance activities. Routine pharmacovigilance
activities are those that are required by the
European law for all authorised drugs, and these
activities are independent from the safety prole
of the drug and any safety concerns in the RMP.
Routine pharmacovigilance activities comprise
the collection, management, and submission of
reports of suspected adverse reactions to the
drug; signal detection, analysis, and management; and preparation and submission of PSURs.
In contrast, additional pharmacovigilance activities are tailored to specic drugs and their safety
concerns and comprise non-clinical studies, clinical trials, or observational studies [83].
Although the analysis of reports of suspected
adverse reactions is probably the oldest pharma-
146
L. T. Bloem et al.
covigilance activity, it is still one of the
cornerstones of today’s pharmacovigilance activities. Even with sophisticated statistical tools for
signal detection in large databases being available and well-designed observational studies
being performed, the analysis of individual case
safety reports (ICSRs) remains an important tool
for rapid identication of new safety signals. A
relevant example in this regard is the identication of the signal of Thrombosis with
Thrombocytopenia Syndrome or Vaccineinduced Immune Thrombotic Thrombocytopenia
associated with the coronavirus disease 2019
(COVID-19) adenovector vaccines, which originated from ve patients who presented with
venous thrombosis and thrombocytopenia
7–10 days after receiving the rst dose of the
ChAdOx1 nCoV-19 adenoviral vector vaccine
against COVID-19 [88].
Apart from the collection and analysis of
ICSRs by drug companies and signal detection in
their own database, the submission by both drug
companies and regulators of all ICSRs to the
EudraVigilance database allows for signal detection by the European regulators in a database
containing over 25.3 million ICSRs, corresponding to 14.8 million unique suspected ADR case
reports, by the end of 2022 [89]. Signal detection
in EudraVigilance includes review of ICSRs, statistical analyses, or a combination of both. For
signal detection with statistical tools, measures
of disproportionality are used and various disproportionality measures are available, such as the
Reporting Odds Ratio (ROR), Proportional
Reporting Ratio (PRR), the Information
Component, or the Empirical Bayes Geometric
Mean [90]. For signal detection in the
EudraVigilance database, both the ROR and PRR
are used, and a signal of disproportionate reporting is then dened with the lower bound of the
95% condence interval of the ROR greater than
one together with a minimum number of cases.
3.5 Periodic Safety Updates
A further routine pharmacovigilance activity is
the preparation and submission of PSURs, which
are also referred to as periodic benet–risk evaluation report (PBRER) [91]. The requirement for
pharmaceutical companies to submit PSURs in
the EU dates back to 1995 [57]. At that time, the
focus of the PSUR was to evaluate whether relevant new safety information had emerged that
would impact the “reference safety information”.
Usually, this is the Company Core Safety
Information and ultimately the authorised product’s product information (the SmPC in the EU).
However, with the new EU pharmacovigilance
legislation that came into force in 2012 [78–80]
and the revision of the ICH Guideline in 2012
[91], the focus shifted from new safety information impacting the product information to new or
changed risks that would impact the drug’s benet–risk balance. This also included new evidence that might impact the effectiveness
(benet) of a drug. Other important changes were
that the new safety data collected during the
period covered by the PSUR should be evaluated
in the context of the cumulative data available,
and that PSURs for drugs that contained the same
active substance were now assessed together, in
the PSUSA procedure. Both changes helped to
avoid that a bigger picture would be missed due
to only pieces of information being considered
every time a PSUR was submitted and assessed.
The format and content of the current PBRER is
described in ICH Guideline E2C (R2) [91], and
the PSUR requested by European authorities follows the PBRER format with an EU-specic
annex.
Before 2012, the periodicity of submission of
a PSUR to European regulatory authorities used
to follow standard intervals with a maximum of a
three-yearly or ve-yearly interval [62, 92]. Since
2012, the submission of PSURs is governed by
the so-called EU reference date (EURD) list, and
the listed PSUR submission intervals are based
on the risk prole of the active substance or combination of active substances contained in the
drug [80]. With this, submission intervals range
from every 6months to 28 years although even
longer cycles would be possible. While the
EURD list is maintained by the EU regulators,
regulators in some other regions accept PSUR
submissions according to the European cycles.
6 Principles ofPharmacovigilance andDrug Regulation
147
While the aim of the PSUR may have changed
from new safety information and its impact on
the product information to a benet–risk assessment at dened points in time, the impact of new
information on the benet–risk balance continues to translate into an amendment of the product information in 15–20% of the PSUR
assessment procedures done at the EU level [89].
These amendments of the product information
can vary from addition of a newly recognised
ADR to the inclusion of new warnings or recommendations that provide new safeguards to avoid
an ADR, decrease its severity, or increase earlier
recognition and thereby prevent progression to
more serious ADRs. Also, safety data from
PSURs can necessitate restricting the use of a
drug in certain patients to protect them from
harm and in such cases new contraindications
may be introduced or the drug’s indication for
use is restricted. Ultimately, if no measures can
be envisaged that would adequately protect
patients in clinical practice, the drug should be
removed from the market. Although such decision can be a result of the evaluation of PSUR
data, in the EU, this is normally taken forward in
another type of regulatory procedure, the socalled pharmacovigilance referral, to allow an
in-depth evaluation of both data on benets and
on risks, with input from clinical experts and
patients as appropriate.
3.6 Post-authorisation Safety
Studies
While routine pharmacovigilance activities are
applicable to all authorised drugs and are independent from the safety prole of the drug, additional pharmacovigilance activities are tailored to
specic drugs and their safety concerns.
Additional pharmacovigilance activities can be
non-clinical studies, clinical trials, or observational studies. In Europe, such studies are referred
to as PASS. Outside Europe, similar studies are
requested by regulators or proposed by drug
companies, with different terminology used such
as post-market studies or post-marketing surveillance studies.
Although the prime purpose of all PASS is to
investigate the safety of a drug that received
authorisation to be placed on the market, they
vary with regard to their precise aim and methodology. Most PASS are performed to contribute to
the understanding of the safety prole of a drug.
This can be the identication of new ADRs, since
the pre-authorisation studies are typically performed in a relatively small, homogeneous and
non-complex group of patients, and for a shorter
duration than how the drug is used in clinical
practice. This limits the identication of infrequent ADRs or adverse events that take longer to
develop or require cumulative exposure to occur.
Examples of those PASS are studies that investigate the long-term safety effects of advanced
therapy medicinal products (ATMPs), such as
gene therapy, somatic-cell therapy, and tissueengineered drugs [93]. Further, PASS may also
be designed to characterise or quantify a specic
safety concern or ADR, in terms of severity, risk
factors or risk population, and frequency of
occurrence. Apart from a limited number of
patients exposed to the drug pre-authorisation for
a limited duration, such PASS may also be needed
as patients with certain comorbidities, worse
health status, or other conditions are excluded
from pre-authorisation studies. Registries in
which pregnant women exposed to the drug are
studied or studies in patients with hepatic or renal
impairment are examples of such PASS.
A completely different type of PASS are those
which are performed to evaluate the effectiveness
of risk minimisation measures. Such studies are
not intended to provide new insights into the
safety prole of a drug but should be able to show
whether the measures that are supposed to mitigate the risks of a drug achieve that objective
when the drug is used in clinical practice.
While PASS can comprise non-clinical studies, clinical trials, or observational studies, most
PASS are observational studies. Data sources for
these observational PASS are often existing databases, such as electronic health record databases,
insurance or claims databases, or disease or pregnancy registries. These databases may be linked
to extend their population coverage or to be able
to link the drug of interest, patient characteristics,
148
L. T. Bloem et al.
and outcomes when these data are not collectively present in one database or registry. PASS
that are clinical trials are mainly studies designed
to investigate the efcacy of a drug but also provide relevant safety information. Notably, not all
post-authorisation studies for a drug are considered a PASS since they should be able to meet the
aim of PASS as dened in the RMP. In view of
the limitations of pre-authorisation studies
referred to above, few post-authorisation clinical
trials can be considered to add signicantly to the
knowledge from registrational studies and allow
further characterisation of safety concerns.
Continuing pivotal clinical trials that are not
completed at the time of authorisation of the drug
and studies in relevant subpopulations could be
PASS, if they are adequate in size, duration, and
ability to capture the safety outcome(s) which
require further investigation. Non-clinical studies
are rarely included as PASS in the RMP since
human data is normally preferred. Yet, in specic
situations where a mechanism of harm is unclear,
but clinical consequences could be signicant on
theoretical grounds, non-clinical studies may be
appropriate PASS as a rst step in better understanding the safety concern in question.
3.7 Post-authorisation Ecacy
Studies
While pharmacovigilance focuses on adverse
reactions and their characterisation and mitigation, the safety prole of a drug is considered in
the context of its efcacy. This allows for monitoring of the drug’s benet–risk balance throughout its entire lifecycle. In the same way as
important gaps in knowledge of the safety prole
may be closed by additional pharmacovigilance
activities such as PASS, PAES can be needed to
close important gaps in knowledge on the benets of a drug or to conrm case ndings from a
single pivotal study. In the EU, imposed PAES,
i.e. those that are required by regulators and
imposed as a condition of the marketing authorisation, became part of the RMP with the European
pharmacovigilance legislation (2012) [78–80]. In
2014, in addition to existing requirements for
PAES for specic drugs—such as those granted a
Conditional Marketing Authorisation (see Sect.
3.8 below), an Authorisation under Exceptional
Circumstances (see Sect. 2.5 above), or ATMPs—
other situations that may require a PAES were
specied. These situations included investigating
clinical outcomes to substantiate already demonstrated efcacy on surrogate endpoints, specic
combinations with other drugs, specic subpopulations, long-term efcacy or if the benet–risk
balance is questioned (i.e. real-life use of the
drug shows that its efcacy might be signicantly
worse than previously evaluated) [94].
The design of a PAES will be tailored to a specic drug and the question regarding its efcacy
that needs to be answered. To provide reliable
estimates of efcacy, randomised studies are the
preferred design for PAES such that confounding
or bias due to non-comparability between groups
is prevented. In certain situations, however, a
non-randomised PAES could be an acceptable
alternative to a randomised study, for example
when randomisation is unethical or unfeasible, or
when outcomes are rare or highly predictable.
These non-randomised studies then need to be
complemented with concurrent comparative data
or, if not available, with historical comparative
data, to allow for a meaningful interpretation of
study results (see Sect. 4.3 below). The role of
observational studies in evaluating drug effectiveness is further discussed in Sect. 4 below.
3.8 Expedited Regulatory
Pathways
A specic case in which PAES and PASS may be
required are the expedited regulatory pathways.
Worldwide, several such regulatory pathways for
marketing authorisation exist that aim to make
promising drugs available to patients earlier.
Well-known examples are the EU Conditional
Marketing Authorisationand the US Accelerated
Approval (see Sect. 2.5 above). Often, earlier
authorisation is achieved by accepting less comprehensive clinical data than for standard marketing authorisation, such as a low number of
patients studied in the pivotal trial(s), a short
6 Principles ofPharmacovigilance andDrug Regulation
149
duration of follow-up of these patients, the lack
of a control to obtain comparative safety and efcacy estimates, or the use of surrogate rather than
clinical endpoints [95–97]. An important prerequisite of these regulatory pathways is that comprehensive data are provided post-authorisation,
often through additional studies such as PAES
and PASS. When these data are ultimately submitted, considered comprehensive and conrm
the benet–risk balance, a standard marketing
authorisation can be granted that is not necessarily subject to additional requirements. While
PAES and PASS must not be used as a justication for premature granting of marketing authorisation or to compensate for the absence of data
on safety or efcacy that are required to demonstrate a positive benet–risk balance at the time
of authorisation, for drugs seeking authorisation
via expedited pathways, the results of a PAES or
PASS may be more critical.
4 Advanced
Pharmacoepidemiological
Approaches forStudying
Safety andEectiveness
forDrug Regulatory
Decision-Making
This section discusses several recent advances in
pharmacoepidemiological methods that leverage
observational or “real-world” data to generate evidence about drug safety and effectiveness for regulatory decision-making. A detailed discussion on
three common observational study designs and the
concepts of bias and confounding is presented in
Chap. 9.
4.1 Signal Detection
As described earlier in this chapter and elsewhere
in this book, spontaneous reporting systems are
the cornerstone of post-authorisation drug safety
surveillance for signal detection (hypothesis generation). Traditionally, routine electronic health
records data and claims data have been used as
data sources to enable conrmation and quantication of drug safety signals (hypothesis testing).
However, during the past decade, these data
sources have been explored as an independent
source to improve and rene signal detection. A
systematic investigation of the complementarity
of spontaneous reporting systems and electronic
health record databases for signal detection was
conducted by the EU-ADR consortium [98]. This
investigation focused on ve selected adverse
events deemed to be important in pharmacovigilance (bullous eruption, acute myocardial infarction, acute pancreatitis, hip fracture, and upper
gastrointestinal bleeding). EudraVigilance identied more signals overall than the EU-ADR databases (41% of signals compared with 32% of
signals). Potential explanations for this difference
included the worldwide coverage of
EudraVigilance compared to the three countries
represented in the EU-ADR databases and the fact
that EudraVigilance was specically designed for
signal detection. Importantly, whether signals
were detected also depended on the nature of the
event: acute myocardial infarction and hip fracture were less likely to be detected by
EudraVigilance compared to the EU-ADR databases, probably because these events are usually
not recognised and reported as ADRs.
Adverse events that are more difcult to attribute to drugs are mostly multifactorial, long-term
(delayed) effects, and those with a high background incidence as was conrmed in large drug
safety monitoring projects such as the
Pharmacoepidemiological Research on
Outcomes of Therapeutics by a European
ConsorTium (PROTECT) [99], Observational
Health Data Sciences and Informatics [100], and
the Sentinel Initiative [101]. Electronic health
records databases may have added value to detect
these adverse events as was demonstrated
recently by Kristensen et al. using the Danish
National Health registries for screening of the
most common cancers in a case–control approach.
From a total of 13,577 drug-cancer associations,
274 were associated with high use and a cumulative dose–response pattern. Of these, 65 were
classied as not attributable to bias, with 20
established as carcinogens by the International
Agency for Research on Cancer. The remaining
45 would require further study to conrm the
association [102]. Using multiple data sources
150
L. T. Bloem et al.
may lead to improved signal detection, but development of this approach requires a deeper understanding of the data sources used, additional
benchmarks, and further research on methods to
generate and synthesise signals [103].
4.2 Multi-database Studies,
Common Protocols,
andCommon Data Models
Traditionally, observational studies have utilised single data sources to assess safety and
effectiveness of drugs. During the past decade,
it became clear that analysing multiple data
sources in parallel offers several advantages
such as increased sample size to detect rare
adverse events, subgroup effects, and early postauthorisation assessment of safety and effectiveness of drugs during a relatively short time
window [104]. Furthermore, the application of a
common (study) protocol, with or without a
common data model, allows the generation of
more consistent results and exploration of
sources of heterogeneity of ndings across data
sources, as further explained below.
Multi-database studies have evolved substantially over the past decade. Initial approaches
comprised of implementing a common protocol
with details on study design, data specications,
and statistical analyses in parallel and locally in
participating data sources [105]. The common
protocol approach was used for instance in a
multi-database study funded by the EMA to characterise the risk of bleeding associated with direct
oral anticoagulants. In this study, four European
databases implemented a common protocol and
estimates of relative risk of bleeding were pooled
across sites. As an extension of this study, the
common protocol was also implemented in the
Canadian Network for Observational Drug Effect
Studies (CNODES) [106] in a collaboration
between the EMA and Health Canada. The results
of these studies have been used by the EMA’s scientic committees PRAC and CHMP to inform
healthcare professionals and patients in Europe
about the use of direct-acting oral anticoagulants.
Their conclusion was that the use of these agents
was safe and effective according to current
instructions for use. A higher risk of bleeding in
patients over 75years of age prompted the EMA
to advise manufacturers to investigate whether a
possible change in dosing advice might be benecial in patients over 75years of age [107].
Subsequent approaches to multi-database
studies developed distributed data networks
that used common data models that generally
include a set of standardised data les and variables, adopted by all data partners participating within the distributed data network. These
also included centrally developed analytical
programmes that are distributed to the data
partners who then share aggregated results for
further meta-analytic pooling of effect estimates [108]. An example of a common protocol—common data model approach was a large
investigation on the risk of myocarditis associated with COVID-19 vaccination. The study
was funded by the EMA and conducted by the
EU PE&PV (Pharmacoepidemiology and
Pharmacovigilance) Research Network in collaboration with VAC4EU (Vaccine monitoring
Collaboration for Europe). The study used the
Conception Common Data Model and used
data from ve European databases. An
increased risk of myocarditis was found, especially when using the Pzer and Moderna vaccines, and specically in people younger than
30years of age who were relatively more often
men. These ndings have been used by the
EMA to educate healthcare workers and the
public about the safety of these vaccines [109].
Several regulatory agencies have formalised
the distributed data network approach as a tool
for drug safety and effectiveness monitoring,
including the FDA with the Sentinel Initiative
[101], Health Canada with CNODES [106], and
most recently the EMA with the Data Analysis
and Real World Interrogation Network (DARWIN
EU) [110]. Sentinel has delivered more than 400
specic drug safety and exploratory analyses
[111]. A recent example of a drug safety analysis
investigated the risk of angioedema following
sacubitril/valsartan in patients with heart failure
using a new-user design matched and stratied
on propensity score [112]. CNODES has com-
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