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6 Principles ofPharmacovigilance andDrug Regulation
151
pleted 56 studies so far [113]. A recent drug
safety analysis in CNODES evaluated the risk of
severe urinary tract infection associated with the
use of sodium-glucose transport protein 2
(SGLT2) inhibitors compared to the use of dipeptidyl peptidase-4 (DPP-4) inhibitors. The conclusion was reassuring given the nding of a reduced
risk of urinary tract infection for SGLT-2 inhibitors compared to DPP-4 inhibitors [114].
DARWIN EU has recently been launched and the
rst study results are being generated [115].
4.3 External Control Groups
Another important development for the monitoring of drug safety and efcacy/effectiveness is
the use of external control groups (or “external
comparators”) to contextualise results from
long- term uncontrolled extensions of clinical trials and single-arm trials. The authorisation of
drugs for rare diseases and novel cancer drugs is
often based on single-arm trials [116] because
of, for example, ethical restrictions to use a placebo or active comparator arm from the same
source population and/or sample size limitations
due to a small available population. In such situations, the use of an external control group may
become necessary to assess safety or efcacy/
effectiveness by providing background rates for
outcomes that can be compared with those in the
single-arm trial. In contrast to an internal control
group that is drawn from the same population, an
external control group should be a group of
patients that is external to the study, of similar
disease severity (at equipoise) but that receives a
different treatment [117]. The external control
group can consist of patients treated at an earlier
time (historical control), or patients treated contemporaneously but in another setting. An
important limitation of using an external control
group is the lack of randomisation, and therefore
the risk of selection and confounding bias [118].
Therefore, the external control group should
closely resemble the inclusion and exclusion criteria, and the treatment and healthcare patterns
of patients in the single-arm trial to prevent
selection bias. When using observational data
sources to select external control group patients,
it should be considered that not all clinical information that is recorded in the single-arm trial
may be recorded in the routine clinical practice
that generated the observational data.
Furthermore, after selection of an external control group, the distribution of characteristics
(especially risk factors for the outcomes of interest) may still be different from the single-arm
trial patient population and result in confounding. Traditional epidemiological methods can be
applied such as matching (either on key confounding factors or propensity scores), or analytical adjustment such as multivariable
regression to control for confounding [119].
4.4 Target Trial Emulation
Finally, an important development during the past
decade was the creation of the target trial emulation approach as a framework for causal inference
to study drug safety and effectiveness. In the target
trial emulation approach, rst, the causal question
needs to be formulated in a protocol of a hypothetical randomised trial that could provide the
answer but for some reason is not feasible. Key
components of the causal “estimand” need to be
dened (eligibility criteria, treatment strategies,
treatment assignment (time zero), the start and end
of follow-up, outcomes, causal contrasts) and the
statistical analysis plan including approaches to
adjust for confounders to emulate random assignment of treatment [120]. The components of the
protocol are then explicitly emulated using observational data, for example, from routine clinical
practice. In some situations, for instance when
there is a lag time before treatment initiation,
immortal time bias can be accounted for by “cloning” of patients. This way, patients can be allocated to both arms of the trial that is being
emulated, after which further analytical procedures can allow unbiased estimation of the treatment effects [121, 122]. The main advantage of the
target trial emulation framework is its transparency and explicit denitions in the different design
and analysis elements of drug safety and effectiveness studies, while preventing common sources of
152
L. T. Bloem et al.
bias. Confounding bias remains an issue that still
needs to be resolved in non- randomised studies
and requires high quality and complete data on
confounding factors. Notably, since blinding of
outcomes and treatment assignment are not possible for observational data, the target trial that is
emulated should be considered a pragmatic study,
that is, a study that compares treatment strategies
as they are applied in clinical practice [120].
5 Summary andConclusions
In conclusion, this chapter covered the series of
historical events such as drug safety crises that led
to the current drug regulatory systems; European
and global drug regulatory harmonisation; the current principles of pharmacovigilance and drug
regulation and advanced pharmacoepidemiological
approaches that contribute to pharmacovigilance
and drug regulation, such as new approaches to signal detection, the use of multi- database observational studies, the use of external control groups,
and the target trial emulation approach. Looking
ahead, important developments can be expected.
First, the entire general pharmaceutical legislation
of the EU will be revised based on a proposal that
was released by the EC in April 2023. The
Commission’s proposal aims to achieve (1) timely
and equitable access to safe, effective, and affordable drugs; (2) an attractive and innovation-friendly
environment for research, development, and production of drugs in Europe; (3) reduced administrative burden by speeding up procedures, thereby
reducing authorisation times; (4) enhanced availability and security of supply; (5) reduced antimicrobial resistance and the presence of
pharmaceuticals in the environment; and (6) more
environmentally sustainable drugs [123, 124].
Although these proposals are not expected to
change the principles of pharmacovigilance and
drug regulation discussed in this chapter, nor how
pharmacovigilance is currently being performed as
laid down in the GVP guidelines, they may change
some of the regulatory procedures that are in place
to assess the benet–risk balance of drugs throughout their lifecycle. Moreover, given the breadth of
these legislative proposals and their expected
impact on the EU’s clinical practice, society, and
pharmaceutical market, they will likely also have a
global impact on drug development and regulation.
Second, even more international collaboration can
be expected, both among drug regulators worldwide to facilitate consistent regulatory decisionmaking based on the same evidence but also with
other stakeholders such as health technology
assessment organisations that provide recommendations about reimbursement of drugs and with
healthcare providers. Eventually, although all these
stakeholders have a different role to play in the
drug lifecycle, they share the same aim: enabling
safe and effective treatments for patients. Increased
mutual understanding and, where possible, alignment of the evidence required for each other’s decision-making process should facilitate faster patient
access to innovative drugs. Third, observational or
real-world data will potentially play a greater role
in providing evidence of a drug’s quality, safety,
and effectiveness, while articial intelligence may
make its introduction in supporting pharmacovigilance, for example, in signal detection.
6 Case Studies
6.1 Case Study 1: Valproate
Valproate and its related substances such as valproic acid and valpromide were rst authorised in
France in 1967 although valproic acid had been
used as a solvent already for years.
1. For which three indications has valproate
since been authorised?
For treatment of epilepsy and bipolar disorders, and in some countries for prophylaxis
of migraine attacks. See for example [125].
After years of use, important ADRs of valproate were discovered that substantially changed
how it has been used since.
2. What ADRs does this refer to?
Congenital malformations such as spina
bida and neurodevelopmental disorders such
as reduced verbal intelligence quotient (IQ) in
children with prenatal exposure to valproate
6 Principles ofPharmacovigilance andDrug Regulation
153
because their mother used valproate during
pregnancy. See for example [126].
3. How often did the EMA advise major regula-
tory actions to address these ADRs and what
were those actions?
Major regulatory actions that were incrementally restrictive to the use of valproate
during pregnancy were undertaken three
times: in 2010, 2014, and 2018.
(a) In 2009, the Dutch Medicines Evaluation
Board requested the CHMP to review
the safety and effectiveness of valproate
in the treatment of manic episodes of
bipolar disorder, the so-called Article 31
referral. In 2010, the CHMP concluded
that use of valproate in the treatment of
manic episodes should be limited to situations where lithium is contraindicated
or not tolerated, and that it should not be
used to prevent recurrence of either
manic or depressive episodes. Moreover,
the CHMP concluded that the use of valproate during pregnancy was associated
with a teratogenic risk, including the
potential for delayed intellectual development. Therefore, the product information was updated to note that valproate
[…] “should not be used during pregnancy and in women of child-bearing
potential unless clearly necessary (i.e. in
situations where other treatments are
ineffective or not tolerated). Women of
child- bearing potential have to use effective contraception during treatment”.
See Ref. [127]. The EC issued a decision
in line with the CHMP’s conclusions.
(b) In 2013, the MHRA requested the PRAC
to review the safety of valproate, specically about the risks associated with use
in pregnant women and “women of
childbearing potential”, through an
Article 31 referral. In 2014, the PRAC
conrmed the risks of congenital malformations and neurodevelopmental disorders and recommended among others
that:
• Valproate “should not be used in female
children, women of childbearing potential and pregnant women unless alternative treatments are ineffective or not
tolerated” in the existing epilepsy and
bipolar disorder indications.
• Valproate should be contraindicated
in the existing migraine indications
in case of pregnancy and in “women
of childbearing potential who are
not using effective methods of
contraception”.
• To inform women and healthcare professionals, the product information
should be updated with further warnings and precautions, and additional
risk minimisation measures such as
educational materials and a DHPC
were needed.
• A drug utilisation study was needed
to assess the effectiveness of the risk
minimisation measures.
See Ref. [128]. The PRAC’s recom-
mendations were endorsed by the
Coordination Group for Mutual
Recognition and Decentralised
Procedures—Human (CMDh) that represents EU member states as overarching
regulatory body for marketing authorisations not granted by the EC.
(c) In 2017, France requested the PRAC to
assess the impact of the previously
instated risk minimisation measures
through an Article 31 referral after
French studies suggested that the 2014
measures were not adhered to. In 2018,
the PRAC concluded that the risk minimisation measures had not been sufciently effective to prevent prenatal
exposure of children to valproate and
recommended among others that:
• The risk minimisation measures
should be strengthened through contraindications for all three indications
in women of childbearing potential
unless the so- called pregnancy prevention programme was complied with.
This included that the patient’s poten-
154
L. T. Bloem et al.
tial to become pregnant should be
assessed, pregnancy tests should be
performed, counselling about the risks
and need for contraception should take
place and periodic review of treatment
should be performed, including the use
of a risk acknowledgement form.
• For the treatment of epilepsy, switching to alternative treatments may in
some instances not be possible.
Therefore, “Every effort should be
made to switch to appropriate alternative treatment prior to conception, and
before contraception is discontinued.
If switching is not possible, the
woman should receive further counselling regarding the valproate risks
for the unborn child to support her
informed decision-making regarding
family planning”.
• For the treatment of epilepsy, use of
valproate during pregnancy is contraindicated unless there is no suitable
alternative treatment.
• For the treatment of bipolar disorders
and prophylaxis of migraine, use of
valproate during pregnancy is
contraindicated.
• Educational materials should be
updated, among others with a patient
card, and a visual reminder of the
risks should be added to the outer
packaging.
• PASS to assess the effectiveness of
the risk minimisation measures
should be performed.
• PASS to assess the risks after paternal
exposure and the risks to thirdgeneration offspring should be
performed.
See Ref. [129]. The PRAC’s recommenda-
tions were endorsed by the CMDh.
4. What was the regulatory goal of these actions?
To prevent that unborn children are
exposed to valproate during pregnancy and
to better inform women of childbearing
potential of the risks of valproate use during
pregnancy. Ultimately to ensure that the
benet–risk balance of the use of valproate
in the authorised indications remains
positive.
5. What was the impact of PASS?
The results of multiple PASS are awaited—
see also the answer to question 6—and independent scientic studies also continue to be
performed and provide insights into the risks
associated with valproate treatment. Recently,
the impact of the 2018 risk minimisation measures and the revised pregnancy prevention
programme on the utilisation and prescribing
trends of valproate was studied [130]. There was
a small impact of the 2018 measures on valproate use in the studied European countries and
regions. The substantial number of concurrent
pregnancies with valproate exposure warranted
a careful monitoring of implementation of the
existing pregnancy prevention programme for
valproate in clinical practice in Europe, to see
if there is any need for additional measures in
the future.
6. Is more regulatory action needed in the
future?
That cannot be predicted. At the time of
writing in October 2023, the PRAC is
assessing the nal study report for a retrospective observational study to investigate
the association between paternal exposure to
valproate and the risk of congenital anomalies and neurodevelopmental disorders
including autism in offspring. “Initial results
of the study may indicate an increased risk
of neurodevelopmental disorders in children
born to men taking valproate in the 3 months
before conception. However, the PRAC has
identied important limitations with the
data from the study” [131]. Furthermore, in
late 2022, the MHRA advised that newly
initiated use of valproate should be restricted
to patients aged 55years and older. See Ref.
[132].
6 Principles ofPharmacovigilance andDrug Regulation
155
6.2 Case Study 2: COVID-19
Vaccines
In December 2019, the SARS-CoV-2 virus
started the COVID-19 pandemic. Thanks to the
development and authorisation of vaccines
against COVID-19, many deaths worldwide have
been prevented and the course of the pandemic
was positively affected [133].
1. When were the rst COVID-19 vaccines
authorised?
The rst COVID-19 vaccines were authorised
worldwide in December 2020.
2. What type of authorisations were initially
granted by the EC, FDA, and MHRA?
The EC granted a ConditionalMarketing
Authorisation. The FDA granted an “emergency use authorisation”, and the MHRA a
batch- specic “temporary authorisation for
supply”. These latter two are not formal marketing authorisations and can be retracted any
time. See for example [134].
3. What were three important common regula-
tory elements that sped up the authorisation
of COVID-19 vaccines?
First, many regulatory authorities performed a so-called rolling review process, in
which they continuously assessed available
data instead of waiting until the entire data
package was available. See for example [135].
Second, regulatory authorities worldwide collaborated intensively, among others through
ICMRA, to enable harmonisation of data
requirements. Third, initial non-clinical and
clinical evidence of safety and efcacy was
used to assess whether the benet–risk balance was positive, while pharmaceutical companies were required to submit data from
additional studies post-authorisation. See for
example [136, 137], and the explanation of
the EU ConditionalMarketingAuthorisation
in Sect. 3.8.
4. How did regulators prepare for post-
authorisation monitoring of the COVID-19
mRNA vaccines?
In response to the COVID-19 pandemic,
the EMA started with preparing for intensied safety monitoring of COVID-19 vaccines. The EMA and national regulators
developed core RMP requirements for
COVID-19 vaccines, which included specic guidance on the post-authorisation
monitoring of COVID- 19 mRNA vaccines.
This guidance addressed, among others,
signal detection and adverse events of special interest (AESI) to be monitored, the
need for observed versus expected (O/E)
analyses, summary safety reports (SSRs) to
be submitted in addition to regular PSUR
reporting and safety surveillance from
ongoing clinical trials and in dedicated
PASS [138]. The safety monitoring carried
out by the EU network throughout the pandemic included near real-time monitoring
of AESI. Real-world evidence from observational studies completed the intensied
safety monitoring to further characterise
emerging safety issues. The EMA contracted in total 11 COVID-19 research projects, one of which was the ACCESS
(vACcine Covid-19 monitoring readinESS)
project. The ACCESS project provided
background rates of AESIs which allowed
the analysis of O/E analyses. Furthermore,
template protocols were developed for different types of research questions and realworld data sources [139, 140].
5. What is the current regulatory status of the
COVID-19 mRNA vaccines?
Full marketing authorisations have been
granted for these vaccines throughout 2021
and 2022 when data from additional studies
was available.
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