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13 Collaborative Approaches toEstablishing andImplementing Pharmacovigilance Systems
307
technical system, and a design challenge as suggested by WHO [35, 46]. Such education and
learning would help not just physicians but also
all HCPs understand how best to balance productivity at work (such as: working with limited
resources of money, time pressures, and adverse
human interactions) and the safety of the patients
while encouraging optimal use of medicines.
Depending on the healthcare institution, the processes should be sensitive to the performance
needs of HCPs, balancing costs while minimising
unacceptable and avoidable risks for patients.
Unfortunately, close attention to culture, systems,
and human factors is still insufciently commonplace in the education of HCPs in many countries
which in turn impacts on the effective use of medicines. Countries should examine the experience
of the UK and US with the role of medication
safety ofcers to assess whether their healthcare
systems would benet from such a role [50, 51].
Professional bodies for HCPs often produce
guidelines which include recommendations
about safe product use. They have a responsibility to incorporate pharmacovigilance both
within ethical and professional codes and into
curricula as well as professional certication
and accreditation. Programmes such as
Prescribing Safety Assessment are a good
example of collaboration between the British
Pharmacology Society and the General Medical
Council to improve education and training
about safe prescribing for doctors in the UK.In
addition, there are prescribers who are not physicians such as pharmacists and midwives in the
UK.They have the responsibility to develop a
basic level of pharmacovigilance competency.
In addition, these societies have the possibility
to inuence public policies and inform the
impartial position of experts in various topics to
help the government to take decisions. It is
important for such societies to have transparent
policies about conict of interest. Some of
these societies produce material that may later
be adopted by regulators to facilitate dialogue
between the regulatory authority and the wider
community (such as recommendations for cardiac resuscitation or management of
anaphylaxis).
12 The Place ofPatient
Organisations andGroups
Patient groups and patients are an important
stakeholder of increasing importance who should,
where possible, be involved in decision-making
such as advisory groups. They will expect as
much transparency as possible behind the basis
of safety decisions. To hear from individual
patients either in hospital or the community,
directly or indirectly through their HCPs, helps
those in pharmacovigilance understand the reality of use for a medicinal product as well as identifying those aspects which are important for
them [52–54]. This may refer not only to suspected adverse reactions about a medicine but
also the consideration of how the medicine has
impacted their quality of life [55]. For example,
some patients (particularly in low- and middleincome countries) with HIV continue living with
stigmas that do not allow them to have the freedom and condence to talk about their treatments
which in turn risks low knowledge, which could
lead to adverse effects too. In addition to the
elderly, the frail, and those with sensory impairment of communication, there are groups of
patients who may be easily overlooked such as
the incarcerated and refugees, who may have special needs and challenges to ensuring access to
safe medicines let alone ensure these medicines
are used properly.
To open channels of easy and free communication between patients and government helps
understand problems arising from the context and
reality of use of medicines for patients. By adding
such information to the results in clinical trials to
help improve decision-making relies on transforming real-world patient experiences into quality data [56]. Sometimes patients nd original
solutions to optimise use of medicines which is
why some hospitals implement peer support to
manage patients. For example, when patients collaborate as peers they can educate each other
about adverse reactions, how to act in case they
suspect an adverse reaction, when they should
seek medical advice or when it is better to remain
calm and wait. To improve patient engagement
must be a priority for understanding what patients
308
B. Edwards and A. Caro-Rojas
need, what they can teach us, and how other stakeholders could contribute to their safety [57, 58].
Recently, CIOMS released a report entitled
‘Patient involvement in the development, regulation, and safe use of medicines’ which they refer
to as a pragmatic handbook summarising our current understanding of best practice [59]. Their
assessment is succinctly summarised as follows:
To date, research on the impact of patient and
public involvement is sparse and it is not known
which strategies are most appropriate. Qualitative
and quantitative research is needed to better
understand what constitutes meaningful patient
and public involvement and how to optimise processes and strategies to obtain the best and most
impactful input from patients and members of the
public. Patient and public involvement rests
mainly on ethical and democratic principles. So
even if we do not yet know what works best in different settings and for each different goal, there is
no doubt that strengthening patient involvement
in all healthcare contexts and taking every effort
to make it meaningful is the way to go.…’
13 The Place ofThose Who Work
inLogistics andSellers
ofMedicines
Everyone who contributes to the logistics and
supply chain has a signicant responsibility in
ensuring safe use of medicines and appropriate
risk management especially concerning product
diversion [60]. For example, should a patient
develop a very strange and unexpected adverse
reaction, the plausibility of which no one can
explain, the possibility of a counterfeit, contaminated, or adulterated product should be considered early on. Good distribution practice with
tracking and tracing of medicines can help shield
patients from the risk of low-quality substituted
and counterfeit medicines. For some medicines,
such as opiate derivatives, diversion for criminal
and abuse purposes is an added risk and additional regulations and safeguards may be needed.
All HCPs need to be exceptionally vigilant in
checking where and how these medicines are
being used and assist in their tracking.
When pharmacists dispense prescribed medicines or sell medicines directly to patients, this is
not merely the last step in logistics and distribution. Pharmacists have a key role in providing
education to patients to ensure proper use of a
medicine, and what they should do in case they
develop certain symptoms after taking their therapy which may be a reportable adverse reaction.
This would include encouraging them to report
concerns through national reporting schemes as
has been set up on the portal of the UK Regulatory
Authority (https://yellowcard.mhra.gov.uk/).
What do we expect from those who are
involved in pharmacovigilance?
To address the shortage in capacity throughout
the pharmacovigilance system it requires explaining what we should expect from all those who are
engaged in pharmacovigilance as a career.
Regardless of the position of the role in the pharmacovigilance system, the authors suggest seeking the following attributes during appointment
which are developed once in post(see Fig. 13.2).
Questioning attitude: They should show an
interest in problem solving and wanting to nd
solutions by showing adaptability and exibility.
Act rigorously and prudently: They should
pay close attention to detail with a desire to establish the facts without cutting corners. A sensible
and honest approach to decision-making and
actions is required in recognising one’s own limi-
.
Questioning
attitude
Fig. 13.2 Skills needed for people who work in pharmacovigilance
Act rigorously
and prudently
Communication
Cooperative and
collaborative
Teamworking
13 Collaborative Approaches toEstablishing andImplementing Pharmacovigilance Systems
309
tations and understanding one’s own role and
how it ts into the system. Prompt management
of errors should be encouraged as well as looking
upon them as an opportunity to learn both for the
individual and for the team.
Communication: They should be careful and
precise with use of terminology such as not confusing an adverse event with an adverse reaction.
This means prompt correction and clarication if
there is misunderstanding about communications
about safety of medicines. Assertiveness is an
asset as knowing how to escalate and to whom
when operational, compliance, or safety concerns
arise. We need individuals who can keep their
manager and team appropriately informed.
Cooperative and collaborative: They
should engage team members and other organisational members in a positive spirit as recognising interdependent and reliance. Being
helpful and polite wherever possible are key
attributes in the stressful environment for many
in pharmacovigilance.
Teamworking: In pharmacovigilance, we
should think of each process in terms of who is in
the team and how we can work together to support each other. We should remember the team
may well extend beyond our own organisation.
Identifying individual and collective strengths
and weaknesses is critical so that measures that
can mitigate risk can be implemented.
Prioritisation on what is important is essential.
We need to recognise the importance of a shared
mental state, collective orientation, and situational awareness especially when these human
factor elements are poorly designed within the
processes for those working within an
organisation.
14 Elements forAchieving
aGood Interaction Among
Stakeholders
Collaboration between all these stakeholders that
we have mentioned is required for product risk
management and effective risk minimisation.
This means helping each participant in the sys-
tem dene their role within the system which
requires stakeholder engagement. Policy recommendations for government, professional societies, and business to achieve these aims are as
follows:
• Inuencing professional education and core
competency training to include pharmacovigilance and risk management
• Integrating technology with uniform application of healthcare IT and app development
with input into design of analytical tools such
as for data queries, data entry, and editing
• Developing new methodologies for available
datasets such as patient outcomes in electronic
health records
• Identifying additional risk minimisation measures for products of public health importance
which have risks not manageable through routine activities
• Prioritising surveillance for newly marketed
products based on agreed criteria
• Intervening for special risk products such as
mandatory education through a register and
reminder schemes; restricted distribution and
performance-linked access such as pregnancy
prevention schemes
• Ensuring there are adequate legislative mechanisms for risk interventions such as authority
to suspend marketing authorisations and protection of HCPs should they wish to report
adverse reactions
• Arranging regular meetings with stakeholders
based on good communication practices
The nal point above concerning good com-
munication is critical so it is worth reecting on
what good principles for collaboration across the
pharmacovigilance system between different
roles might look like:
Open and transparent communication: The
ethical, legal, and regulatory environment
requires that the interests of each stakeholder
should be declared (most of which may be totally
legitimate and uncontroversial) with specic
conict of interests being revealed when a particular safety situation is under review.
310
B. Edwards and A. Caro-Rojas
Condence to speak up: When interests are
declared in a just and fair culture, then this builds
condence between stakeholders to enable frank
and open discussion. Such condence requires
time to build, and human interactions and performance should be monitored to ensure that all
stakeholders are behaving with transparency,
objectivity, and adherence to safety objectives.
Creating a focus on common goals aligned
with healthcare priorities: It is important for
the stakeholders to dene specic goals for their
own country and region bearing in mind the following points:
• Although patient safety is the most important
goal, different stakeholders may have legiti-
mately different interpretations as to what that
means. Ideally, this should be supported with
evidence using systematic reviews and real-
world studies about effectiveness.
• To understand that every stakeholder has con-
ict of interests and the best scenario all
should seek is a win-win situation requiring
sensitive negotiation with attention to detail.
Stakeholders should recognise that compro-
mise may be required, or else accessto medi-
cal products can be impaired and excessive
burden on healthcare system introduced with
unintended consequences.
• To understand that medication risk is a sys-
temic problem and not solely an individual
responsibility.
• Identify and agree on what are avoidable
important risks and how much effort should be
spent to minimise them.
• To share wherever possible relevant informa-
tion in the interests of patients recognising
that some stakeholders will have genuine pro-
prietary concerns.
15 Summary andConclusions
The concept, scope, and practice of pharmacovigilance has developed considerably since its
inception in the 1960s. We now understand that
pharmacovigilance encompasses all aspects of
evaluation of drug safety across the life cycle
including monitoring clinical investigation as
soon as a medicine enters humans and extends
into how medicines are used in clinical practice.
A proactive, systematic, and investigative
approach is necessary in pharmacovigilance
using a variety of methods of surveillance and
evaluation. At all phases, key objectives of pharmacovigilance remain identication of new hazards or changing safety proles, taking actions to
improve safe use of medicines and communications of all matters concerning drug safety to all
end users including patients. These actions
underpin benet/harm assessment as part of clinical safety pre-authorisation, assessment at the
time of granting a marketing authorisation and
then continues as post-authorisation development
including progress to change of legal status from
prescription only to pharmacy and over-thecoun ter status [61].
Although regulation is important and necessary, it alone cannot create good quality pharmacovigilance. We must take a systems
approach incorporating all stakeholders with
patients at the centre. Such a pharmacovigilance
system can be understood as a combination of
three subsystems based on information collection/data management, analysis/signal detection, and interventions to manage risk [62].
Thus, our understanding of the scope of pharmacovigilance systems extends beyond the scientic risk of medicines and devices and
includes risk when humans in the real world use
these products in clinical environments and
ambulatory care such as in homes and community residences. This means pharmacovigilance
involves more than just the regulator or company who is legally accountable for a medicine’s
safety but also the wider community in general,
including addressing the vision and wishes of
patients and their families. Each HCPhas a key
role in advising and implementing ideas about
risk minimisation, how best to communicate
among stakeholders the possibility of risk and
why measures to protect patients are needed.
Finally, it is the patients and their clinicians who
should decide ultimately whether amedicine is
effective or not, and its safety prole is
acceptable. They have a responsibility to know
13 Collaborative Approaches toEstablishing andImplementing Pharmacovigilance Systems
311
what to do should they suspect an adverse reaction, or a medication error has occurred to a
medicine and how they should notify the appropriate authorities.
Despite the considerable progress in pharmacovigilance and risk management, there remain signicant questions which require more in-depth
and detailed collaboration between stakeholders to
help us resolve them. We all know that ‘safety is
everybody’s responsibility’ but what does that
mean? What is meant by risk-based compliance?
What is the basis for an effective safety system?
How can we facilitate reporting of meaningful
information about medicines? These questions
reect changing values and attitudes in society
towards risks and human rights so these must be
kept under review. Ultimately, the solutions to
many avoidable risks with medicines result from
humans working in complex systems, where they
will make what appear to be medication errors (or
so it may seem although often what we call ‘errors’
reect what most people would have done under a
certain set of circumstances). This is because ultimately the safe use of medicines and devices
depends on human performance. This is not just
the performance of the end user, such as the prescribing healthcare professional and their patients,
but all who contribute to the pharmacovigilance
system from the governing bodies at the top to the
end users at the bottom of the hierarchy.
There is now overwhelming evidence that
most of what is referred to as non-compliance
and unsafe use of a medicine or device can be
explained by understanding human factors and
system design which can be referred to as organisational science. There is good news as the science around human factors has expanded in the
last 20 years so that there is a vast amount of evidence that can be examined [63]. We now better
understand the importance and relevance of topics such as situational awareness, leadership,
communication, error management, understanding the impact of personality on human performance and safety behaviour, and nally, safe
decision-making [63]. In addition, there are
already those individual professionals scattered
throughout the global pharmacovigilance system
with excellent human factors skills who have
been struggling individually to make the system
more effective when they can exert inuence.
The problem is that this piecemeal approach
means that standards for making human factors
the centre of process design have not been systematised or recognised for their importance.
Indeed, there are no globally accepted principles
to achieve a global system to optimise use of
medicines [64]. In the absence of internationally
agreed guiding principles, it will remain challenging for the wide array of stakeholders to
cooperate and collaborate both within and
between national systems for ensuring safe use of
medical products.
To our knowledge, there has been little emphasis on system design and organisational sciences
in pharmacovigilance curricula and training.
Training in the industry and elsewhere concerning safety of medical products is all too often
focused only on documented standard operating
procedures although these documents are only
part of the process and all features of a process
require attention in pharmacovigilance. No
organisation can afford to ignore human factors
given that they are often primarily responsible for
many examples of process breakdown. There is
an urgent need to optimise human performance
within the pharmaceutical sector for patient
safety and efciency with systematic implementation of situational awareness, safety leadership,
communication, error management, team working, understanding the impact of personality on
human performance and behaviour and nally,
safe decision-making.
Human factors encompass all those factors
that can inuence people and their behaviour in a
work context. Human factors include environmental, organisational, and job factors, as well as
individual and team characteristics which inuence behaviour at work as the basis for safety and
efciency. We strongly believe that through an
understanding of the effects of teamwork, tasks,
equipment, workspace, culture, organisation on
human behaviour, perception, motivation, and
overall ability, and the effective application of
that knowledge in all pharmaceutical settings and
processes, this will enhance performance and
maintain safety with a just system that will
restore and promote dignity and fairness to all
participants.
312
B. Edwards and A. Caro-Rojas
Human factors training needs to be fully integrated into medical, pharmaceutical, nursing, and
other healthcare professional curricula in the
teaching and training of tasks and activities. It is
not an add-on as a ‘soft skill’ which is ‘nice to
have’. Such an understanding of human factors is
archaic and must be discarded; in reality, effective use of non-technical skills can take great
moral courage. An effective human factors
approach must similarly apply to all respective
regulatory bodies. Systems and organisational
science should be developed as a healthcare speciality with sponsorship of research into systems
science for safety of healthcare products.
Adoption of human factors needs top-down and
bottom-up buy-in and needs to be fully embedded in all aspects of healthcare. This includes initial training for the current workforce in the
short-term and tighter integration into the training of all future healthcare workers from the
outset.
In conclusion, our approach in pharmacovigilance should focus on system design, the product,
and all individuals and how human factors affect
the functioning of all based on guiding principles.
There is more to this than merely regulatory compliance. The fewer the resources, the more important understanding and applying human factors
and quality becomes.The cost of not doing so is
high.
16 Case Studies
16.1 Case Study 1 [65]
Clozapine is prescribed for severely ill schizophrenic patients who fail to respond adequately
to standard drug treatments for schizophrenia.
However, through spontaneous reports, it was
noted that a life-threatening adverse reaction,
agranulocytosis (an absolute neutrophil count
<500/cumm), which can lead to fatal sepsis,
could occur commonly with a cumulative incidence of 1.3%. But treatment-resistant schizophrenia is a very serious life-threatening
condition for both the patient and those around
them so measures had to be implemented so that
clozapine could be kept on the market safely.
Early detection of agranulocytosis and treatment
interruption would be the aim of a risk mitigation
strategy.
1. Is there a widely available blood test to detect
a fall in white cell count early?
Yes, measurement of full blood count is
widely available. However, all stakeholders
need to be made aware of the strategy.
Haematology laboratories need to be able to
identify samples from patients on clozapine
and put processes in place to feedback white
cell count results promptly to pharmacists so
they can dispense clozapine.
2. Can the strategy rely on routine pharmaco-
vigilance or are additional measures
required?
No, relying on routine practices and surveillance is inadequate. A national patient register is required of patients receiving clozapine
typically monitoring for agranulocytosis
weekly during the rst 3 months after a rst
prescription or after restarting after a pause
following leucopenia. After 3 months,
monitoring can be adjusted as the risk falls
with further adjustments after 6 months as the
risk declines further. The MAHs set up the
registry which is approved by the regulatory
authority. However, cooperation is essential
of prescribing psychiatrists, HCPs who
arrange for blood test monitoring, haematology laboratories and pharmacists to ensure the
register is a success.
3. Does the register replace the normal surveil-
lance responsibilities of HCPs?
No, HCPs must still be vigilant for worrying and unexpected adverse reactions which
they should report to the MAH who is responsible for the register. This means that those
who prescribe and dispense clozapine should
have the MAH contact details readily available. The MAH must compile periodic reports
for its supervising regulatory authority reporting all abnormal white cell counts and other
serious or unexpected adverse reactions.
13 Collaborative Approaches toEstablishing andImplementing Pharmacovigilance Systems
313
4. How are HCPs supposed to nd out about a
clozapine register?
MAHs prepare Dear Healthcare
Professional communications which must be
approved by the supervising regulatory
authority. The MAHs often may consult with
and inform professional societies and patient
groups about their plans for a register to obtain
feedback about feasibility and burden. The
Summary of Product Characteristics will be
kept up to date with monitoring instructions to
reduce risk so that HCPs should know where
they can access the latest version.
16.2 Case Study 2 [17]
Terfenadine was a non-sedating H1 Receptor
antagonist for the relief of allergic rhinitis symptoms, which was very popular as an over-thecounter medicine as its non-sedating properties
were widely welcomed so that there were blockbuster sales. Around 1992, studies were published showing that metabolism of terfenadine
could be blocked by drugs inhibiting hepatic
enzymes metabolising cytochrome P450
(CYP)3A4 and that resultant accumulation of the
unmetabolised parent drug led to serious cardiac
abnormalities including QT prolongation and torsade de pointes.
1. What immediate action needs to be taken
when new risk evidence occurs for an overthe- counter medicine such as terfenadine?
When major risk factors have been identied then advice for prescribers and users
should be modied. As a result, in 1992, the
existing warning statements in the SPC about
concomitant use of terfenadine with ketoconazole or macrolide antibiotics or in hepatically impaired patients were elevated to
contraindications. This regulatory action was
supported by press releases and HCP communications. For labelling changes alone to
reduce risk requires the cooperation of prescribing HCPs, dispensing pharmacists, and
patients to check whether the requirements for
safe use have changed and what they are
expected to do.
2. Can society rely on spontaneous reporting to
monitor the impact of changing the warnings
and contraindications in the approved product information?
Spontaneous reports are an excellent
source for signal generation but cannot be
relied upon for monitoring the potential for
drug interaction. Epidemiological database
studies (such as pharmacy claims and health
insurance databases in the US) showed substantial declines in use of contraindicated
medicines with terfenadine after the labelling
change although concurrent use of terfenadine with contraindicated drugs continued.
However, heightened vigilance by HCPs
meant spontaneous reports of malignant ventricular arrhythmias and sudden death continued to be reported.
3. Electrocardiograms (ECGs) can be used to
measure QT intervals, and these are widely
available so that ECG monitoring should
help, shouldn’t it?
Terfenadine is used in the community so
that regular monitoring using ECGs would
not be practical. Prevention of high-risk drug
interactions was the essential part of managing
risk. That is why as spontaneous reports of
serious ventricular arrhythmias continued,
terfenadine was returned to prescriber only
status so that prescriptions could be better
controlled.
4. Medicines with serious risks can often be sup-
ported on the market by collaboration between
stakeholders. How did the benet–harm of
terfenadine become so negative that revocation of the marketing authorisation was
required?
The indication for terfenadine, allergic rhinitis, is not a life-threatening or medically
serious condition although it can be very distressing for patients Thus, in its own right
having life-threatening risks put the medicine
under regulatory pressure. However, what
really pushed terfenadine off the market was
the arrival of safer alternatives. In particular,
314
B. Edwards and A. Caro-Rojas
in 1997, the active metabolite fexofenadine
was approved and then plans to withdraw terfenadine announced. The arrival of an alternative product can be a game changer for the
benet–harm evaluation of a medicine already
under scrutiny. When there is a comparable
access and efcacy but without the known
harms, then justication for retaining a product rapidly disappears. Indeed, in reality, regulators rely on prescribers to show good
judgement and turn to the safer product(s)
which is what happened with terfenadine.
16.3 Case Study 3 [66]
Cisapride was approved in 1993 for nocturnal
heartburn in adults with gastrooesophageal reux
disease. However, this specic indication led to
extensive off label use for all sorts of heartburn
without needing to demonstrate reux, as well as
other gastrointestinal disorders thought to be
caused by dysfunctional motility. Through spontaneous reports, serious cardiac arrhythmias (such
as torsades de pointes) were identied. Following
regulatory requests, the MAH performed preclinical studies which in 1998 showed a direct effect of
cisapride on cardiac conduction.
1. In what way can new approaches from clini-
cal pharmacology help us explain newly identied adverse reactions?
The serious cardiac arrhythmias associated
with cisapride coincided with our evolving
pharmacological understanding of the relation
of the hepatic cytochrome system to metabolism and how the effect of medicines on QT
interval could be better investigated preclinically. For marketed medicines, new nonclinical and pharmacology data can continue
to be produced which can impact causality
assessment of spontaneous reports thus
strengthening signals.
2. What were the aims of the initial risk manage-
ment actions for cisapride?
As with terfenadine, the original targets for
managing risk with cisapride focussed on
strengthening warnings about drug interac-
tions leading to contraindication with drugs
known to prolong QT interval or in patients
who may have disorders that predispose to QT
interval prolongation. This meant HCPs had a
critical role in understanding the relevance of
this new information and how these changes
impacted prescribing and dispensing.
3. What role did academia play in assessing the
effectiveness of risk minimisation actions for
cisapride?
When the serious cardiac safety concerns
were raised for cisapride this motivated development of epidemiological assessment by
academia using different healthcare databases
and methodologies. Between 1998 and 2000,
there were several epidemiology studies
assessing whether co-prescribing of cisapride
was reduced which reached different conclusions. The pharmacovigilance regulator has
an important role in collating epidemiological
data and helping drive concepts such as metanalysis and the optimum way to perform this.
4. How did the changing science about gastroin-
testinal motility impact the benet–harm of
cisapride?
The important role of Helicobacter pylori
in gastroesophageal disease and the rise of
proton pump inhibitors fundamentally
changed treatment of upper gastrointestinal
disorders. This was especially deleterious for
cisapride as the macrolides were treatment of
choice for Helicobacter pylori and yet they
were contraindicated with cisapride. In addition, gastrointestinal motility theories to
explain other disorders became less fashionable. As HCPs better understood the science,
scientic societies changed their guidelines
against the use of cisapride dramatically driving down use. These changing opinions about
pathophysiology had a more powerful impact
on limiting harm from cisapride than regulatory action on indications, which is often a
next step once the options of warnings and
contraindications have been exhausted. In the
EU, a restricted access register has been created to maintain supply of cisapride to those
patients who need it under strictly controlled
conditions.
13 Collaborative Approaches toEstablishing andImplementing Pharmacovigilance Systems
315
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