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Pharmacovigilance
Good Pharmacovigilance
Principles and Considerations for
Biotherapeutic Medicines
C ontents
Section Page
Pharmacovigilance: 1
Reasons for Reading On
1 Pharmacovigilance and 2
Biotherapeutic Medicine
2 Importance of Traceability for 4
Biotherapeutic Medicines
3 Adverse Drug Reaction 6
Collection and Signal Detection
4 Risk Management Plans and 9
Risk Minimization Elements in
the Pharmacovigilance System
5 Roles and Responsibilities 11
of Stakeholders
6 Global Signal Detection 14
Summary 15
Glossary 16
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 1
Pharmacovigilance:
Reasons for Reading On
Everyone should understand the value in reporting side effects
of medicines. This is an important measure by which the safety of
medicines for, and treatment of patients worldwide can be improved.
Less is further known about how reporting actually happens, what
may prevent reporting from happening effectively and what is done
with the data once collected. Collectively, these activities are referred to
as pharmacovigilance (PV), and we all have a role to play in delivering
effective PV.
In order to anticipate, identify, record and report side effects, we first
need to have a good understanding of the medicines themselves.
Biotherapeutic medicines (or biotherapeutics) are complex and
have unique characteristics; therefore they require appropriate PV
monitoring. The purpose of this brochure is to help outline the
challenges, explain how PV practices can address these challenges
and describe the different roles we all have in contributing to effective
monitoring for safe medicines use.
2 Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines
Pharmacovigilance and
Biotherapeutic Medicine
The World Health Organization (WHO) describes “pharmacovigilance” as “the
To provide some context for what this
science and activities relating to the detection, assessment, understanding and
means in practical terms, the European
prevention of adverse effects or any other drug-related problem.”1 PV systems
Commission has defined the following
are widely recognized as important tools in the regulatory process for medicines,
expectation for EU Member States to
for protecting public health and an integral component of patient healthcare. enact at the national level:
The WHO describes a national PV system “as an obligatory investment in the
future public health of the territory.”2 European Commission Directive
2010/84/EU:6
It is impossible to completely characterize the safety profile of a new medicine (e) ensure, through the methods for
through clinical investigations before the first marketing authorization is granted. collecting information and where
PV is necessary as it allows health authorities to continue to assess benefit/risk necessary through the follow-up of
throughout the life-cycle of a medicine and potentially detect rare and serious suspected adverse reaction reports, that
adverse drug reactions (ADRs) that were not detected before marketing all appropriate measures are taken to
authorization. PV can also identify new safety signals related to product quality identify clearly any biological medicinal
and/or changes in use and prescription patterns. In order to do so it is important product prescribed, dispensed, or sold
in their territory which is the subject of a
that a robust national PV system is established.
suspected adverse reaction report, with
However, maintaining a robust PV system relies on consistent and accurate due regard to the name of the medicinal
acquisition, integration and analysis of ADR data.3,4 Without such a strong product, in accordance with Article 1(20),
foundation important safety signals can get hidden, confounded or diluted. and the batch number;
Moreover for any given medicine used across the globe, it is imperative that
ADRs are collected, safety signals identified and analyzed in a comprehensive
way, combining the output from multiple national PV systems. To that end,
the WHO Program for International Drug Monitoring was set up in 1978 and is
delivered by the Uppsala Monitoring Centre.5
1 WHO (2014) Essential Medicines and Health Products: Pharmacovigilance. World Health Organization,
February 3, 2014 [online].
http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/
2 The Safety of Medicines in Public Health Programmes: Pharmacovigilance an essential tool, 2006.
3 The WHO has created guidelines for pharmacovigilance systems that can be found through the
following link:
http://www.who.int/medicines/areas/quality_safety/safety_efficacy/Pharmacovigilance_B.pdf
4 WHO has also endorsed a web-based toolkit, developed by pharmacovigilance experts, reviewed
by the Uppsala Monitoring Centre and funded by the Global Fund, that can be found through the
following link: http://pvtoolkit.org/
5 “As of October 2013, 117 countries have joined the WHO Programme for International Drug
Monitoring, and in addition 30 ‘associate members’ are awaiting full membership while compatibility
between the national and international reporting formats is being established.” World Health
Organization, February 3, 2014 [online].
http://www.who-umc.org/DynPage.aspx?id=98080&mn1=7347&mn2=7252&mn3=7322&mn4=7324
6 The European Parliament and the Council of the European Union (2010) Directive 2010/84/EU of the
European Parliament and of the Council. The European Parliament and the Council of the European
Union, January 6, 2015 [online].
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 3
Key Principles
• All medicines have the
potential to cause ADRs.
Biotherapeutic medicines have
unique product characteristics,
due to their biological nature
and complex structure that
require individual product ADR
tracking. Certain events which
may be too rare to be detectable
during clinical trials prior to the
marketing authorization can
lead to ADRs or even decreased
While this need for a strong foundation is common to all medicines, it is efficacy.
especially so for biotherapeutic medicines.7,8 The specific characteristics of
such complex products immunogenic potential require more emphasis on PV
monitoring. Regulators in the European Union (EU) have put mechanisms in
place to strengthen PV monitoring to ensure accurate attribution of ADRs and
the medicinal product.9 The United States Food and Drug Administration (US
FDA) has made similar suggestions in their draft biosimilar guidance issued in
February 2012.10
A recent discussion on PV for biotherapeutic medicines at the Brookings
Institution in Washington D.C. summarized the imperative: “PV systems depend
on the accurate identification of individual products and an ability to link
exposure to possible adverse outcomes.”11 This challenge becomes more difficult
in a global environment with multiple sources of a given class of biotherapeutic
medicine, including biosimilars and other biotherapeutics that have been
authorized under different regulatory pathways. Product-level traceability is a
core objective for PV systems for biotherapeutics medicines; the challenge is
how to achieve this within countries and how to connect these systems globally
so that safety signals are quickly and correctly identified and assessed.
7 Giezen et al. Safety-Related Regulatory Actions for Biologicals Approved in the United States and the
European Union. JAMA, 2008; 300(16): 1887
8 Giezen, T., et al. (2009). Pharmacovigilance of Biopharmaceuticals. Drug Safety 32(10): 811-817.
9 Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010.
Official Journal of the European Union. 2010;348:1-16; Directive 2010/84/EU of the European Parliament
and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/
EC on the Community code relating to medicinal products for human use.
10 FDA. Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference
product (February 2012); section VIII.
11 Engelberg Center for Health Care Reform at Brookings, Developing Systems to Support
Pharmacovigilance of Biologic Products: Discussion Guide (Nov. 15, 2013) (Brookings Paper).
4 Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines
Importance of Traceability for
Biotherapeutic Medicines
As highlighted in the previous section, accurate identification of an individual biotherapeutic
medicine and manufactured batch is one of the pillars of a good PV system. Because of their
complexity, biotherapeutics may cause unwanted immune responses, which differ in range
and severity and sometimes are difficult to identify quickly. The complex production process
of a biotherapeutic partly determines the characteristics of the end product, and this process
is tightly controlled for consistency. When changes occur in the process, either intentionally
or unintentionally, this has the potential for triggering ADRs, which can occur up to many
months after initiation of treatment. Therefore, more than for conventional chemically-
synthesized small molecule medicines, post-approval follow-up on an individual product
level is essential. Full traceability requires not only that the ADR report can be allocated to
one particular biotherapeutic medicine and given batch, but also that it is verifiable that this
is indeed the same product that was originally dispensed to the patient (see Figure 1).
Prescribing Dispensing ADR Reporting
Globally Globally Globally
distinguishable distinguishable distinguishable
Batch number Batch number
Figure 1: Full traceability throughout the prescribing,
dispensing and ADR reporting chain
To achieve product-level traceability for biotherapeutics, clear identification and
recording is needed. A fundamental measure for identification is the use of a
distinguishable name, which is used consistently around the world and yet unique for
each individual biotherapeutic medicine. Batch number is also an important identifier
for traceability, and has proven particularly useful for identifying batch-related ADR to
a product belonging to one Marketing Authorization Holder (MAH). However, recent
experience in some regions demonstrates that batch numbers are not as frequently
recorded in ADR reports.12 Therefore, additional means of identification and recording
are needed at all steps of use: through prescription, dispensation, record-keeping,
ADR reporting and signal analysis to ensure that a link can be made between an ADR
reported in any jurisdiction and the exact product dispensed to that patient.
12 Vermeer, N., et al. (2013). Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: A Cross-Sectional
Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance Databases. Drug Safety 36(8): 617-625.
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 5
If ADR occurs If ADR occurs Key Principles
INN only Brand and INN
• Each biotherapeutic medicine
Physician Physician prescribes including biosimilars should
prescribes by brand and be required to have a
by INN only distinguishable distinguishable name that
INN clearly differentiates it from
other biotherapeutic
medicines. This will ensure clear
identification, safe prescription
Pharmacist P harmacist
and dispensing to patients,
dispenses an dispenses
available or cheapest s tated brand or and enable accurate reporting
biotherapeutic contacts physician and analysis of ADR data (i.e.,
with same INN to agree change improve traceability).
• It is very important that
Reporter does In event of an healthcare professionals are
NOT have ADR reporter knows educated and encouraged to use
immediate access exactly which the distinguishable name when
to precise product product the patient prescribing and dispensing to
given to patient was dispensed ensure that any ADRs reported
are assigned to the correct
biotherapeutic medicine and
It is unclear Physicians know batch number.
which medicines which drugs are
are linked linked to ADRs
to ADRs
Prescribing by brand name and distinguishable
International Nonproprietary Name (INN) allows
physicians rapid access to the precise product
dispensed when reporting ADRs
Source: Amgen
Figure 2: In a multisource environment, distinguishable names ensure
traceability
Loss of traceability can occur for a number of reasons. An example is given in Figure 2.
Figure 2 describes the impact when a medicine is prescribed in an environment where
separate products are marketed using the same non-proprietary name and the physicians
and pharmacists do not record a distinguishable name for what is prescribed and dispensed.
Subsequently a reporter, who could be the prescriber or patient, needs to associate a side
effect with the drug dispensed and report to a company or national regulatory agency (NRA).
6 Good Pharmacovigilance Principles and Considerations for Biotherapeutics
ADR Collection and
Signal Detection
A second important pillar of PV is the ability to link exposure to possible adverse
outcomes.13 This is done through a process called signal detection. As described
previously, the ability to conduct PV is an important tool for health authorities to
continuously assess the benefit/risk throughout the lifecycle of a medicine. Product
development and subsequent authorization aims at making medicinal products
available that have been demonstrated to be effective and safe. At the same time,
however, it is important to ensure that medicines are made available as quickly as
possible to patients that need them. There needs to be a good balance between
the amount and type of data (e.g. survival data, pharmacodynamic endpoint) that
need to be available prior to authorization and the data that can be generated after
approval (e.g. higher number of patient exposure). With increasing complexity of
the products involved, this balancing act becomes more important, recognizing
that clinical studies during the development of a medicine will never be able to fully
provide certainty. Thus, national regulatory agencies (or regulators) and industry are
constantly looking for more risk-based approaches that allow earlier access while
still ensuring adequate efficacy and safety. Such approaches rely on additional data
being generated post-marketing authorization approval to inform on defined and
acknowledged uncertainties remaining at the time of marketing approval and to
confirm the benefit/risk profile in clinical practice.
Because of the variety and rarity of ADRs that can be anticipated for biotherapeutic
medicines, PV systems need to be suitably sensitive to identify changes in ADRs
with respect to incidence, type and severity and to be able to correctly link these
signals to products. Several PV techniques are available, spontaneous reporting
of ADRs being the most widely and globally used. Other, more complex methods
such as medical registries or retrospective analyses of existing databases can be
used in addition, to focus on a certain product (class) or on an event. Many products
of biological origin, especially those intended for serious diseases, use registries to
follow the patient population in more detail.
The most widely used method of PV relies on spontaneous reporting of suspected
ADRs and many important safety signals have been picked up in this way. Drawbacks
of spontaneous reporting include underreporting, incomplete information, and
sensitivity to known or unknown external factors.14 Furthermore, the vast number of
spontaneous reports received makes case-by-case analysis and medical evaluation
more and more challenging and specific tools have therefore been developed to
13 Engelberg Center for Health Care Reform at Brookings, Developing Systems to Support
Pharmacovigilance of Biologic Products: Discussion Guide (Nov. 15, 2013) (Brookings Paper).
14 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP).
Guide on Methodological Standards in Pharmacoepidemiology (Revision 1).
Good Pharmacovigilance Principles and Considerations for Biotherapeutics 7
help identify patterns in the data (e.g. disproportionality analysis).15,16 To facilitate
aggregated analysis of the data, spontaneous ADR reports are collected in databases.
However, these databases may have some limitations too (e.g. reporting practices of
the countries that submit the data to the database may differ considerably or time
difference between the occurrence of the event and the availability in the database).
Example of Databases
WHO International Drug Monitoring Program Vigibase
http://www.umc-products.com/DynPage.aspx?id=73590&mn1=1107&mn2=1132
US FDA ADR Reporting System for Pharmaceutical Products (FAERS)
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Surveillance/AdverseDrugEffects/default.htm
Eudravigilance Database in the EU
https://eudravigilance.ema.europa.eu/highres.htm
A registry is an organized system that uses observational methods to collect uniform
data on specified outcomes in a population defined by a particular disease, condition
or exposure.17 Ideally a registry will contain a control group and should not only
include patients being prescribed a specific product. As for spontaneously reported
data, in practice, recorded data can be inaccurate or incomplete. Furthermore,
participation in a registry is voluntary and will vary by practice or institution.
Registries do not stand on their own; they are used as a data source within which
(epidemiological) studies can be performed, keeping in mind guidelines for good
pharmacoepidemiology. In addition, ADRs reported in a registry will also be dealt
with as spontaneous reports and end up in one of the databases described above.
Whether signals originate from the monitoring of data from spontaneous reporting
or from data originating from other sources can be based on a number of ADRs
received over a defined period of time for a defined drug substance or medicinal
product. Higher reporting than expected for the active substance or product
of interest is considered to be a signal, which has to be further investigated and
validated. The ‘expected’ reporting rate can be related to all other active substances/
medicinal products in the database. The principles of these calculations are shown
in Figure 3. The larger the database, the more representative the ‘expected’ reporting
rate will be. But it can also be easily seen from this figure that misclassification of
one or more ADRs can lead to a substantial shift outcome, which could make the
difference between a signal or no signal, in particular when the ADR is rare.
15 Almenoff JS, Pattishall EN, Gibbs TG, DuMouchel W, Evans SJW, Yuen N. Novel statistical tools for
monitoring the safety of marketed drugs. Clin Pharmacol Ther 2007;82:157-66.
16 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Guide on
Methodological Standards in Pharmacoepidemiology (Revision 1).
17 Guideline on Good Pharmacovigilance Practices (GVP) – Module V, EMA/838713/2001.
8 Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines
Key Principles Follow-up information
• PV reporting systems should
be easy to use to allow reporting Reporter
MAH
by any party including patients
and HCPs and well-structured to
facilitate the meaningful analysis HCP
of ADR data on biotherapeutic Login internal
medicines. database
NRA
Assess & Report as
• Health authorities, national Complete required
regulatory agencies, medical Consumer External
researchers and companies Databases
should be able to perform
HCP = Healthcare Professional
analyses at both the product NRA = National Regulatory Agency
class (e.g. epoetin) and MAH = Marketing Authorization Holder
individual product level (i.e.
separated by manufacturer or
MAH) for each biotherapeutic
medicine. Check for missing Input Product
information; Brand name
Follow-up with if available
reporting
Check for Assess
validity; seriousness
Include ADR in & relatedness;
company When in doubt:
database related
Source: MSD
Figure 3: Reporting path of and ADR from reporter to final database
If an unexpected ADR with a particular product does occur, early signal detection
and subsequent rapid assessment and validation are important. This will allow
quick and targeted action (e.g. risk minimization through a change in the product
information, communications to healthcare professionals (HCPs) or even a temporary
withdrawal of the product from the market). The longer it takes to pick up the signal,
the more patients will have been exposed and be at risk. When searching for signals,
therefore, the limitations of the dataset play a role to determine the evidentiary
value. For these reasons, signal detection should follow recognized and robust
methodology and a multidisciplinary approach, including statistical analysis that is
appropriate for the data set. Proof of causality will always require additional evidence
to be generated.
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 9
Risk Management Plans
and Risk Minimization
Elements in the PV System
At the time of regulatory approval, the safety information about a medicine is
still relatively limited compared to the information that will be available when
the medicine is actually used in healthcare practice over the years. The evidence
compiled for regulatory approval may identify known or potential safety risks for
patients, based on the preclinical and/or clinical study results. There may also be
missing information, which is defined as “critical gaps in knowledge for specific safety
issues or populations that use the marketed product”18.
The company responsible for a biotherapeutic medicine usually agrees with the
approving regulatory authority on a safety plan, known as a risk management plan
(RMP), to address this need to further collect and analyze the safety data for a given
medicine – its known and potential risks and any missing information.
The European Medicines Agency (EMA) recently summarized the scope
of a RMP as a defined set of PV activities which:
• Aim to characterize the safety profile of the medicine
• Proactively plan activities to characterize risks and to identify new risks
and increase knowledge about the safety profile of the medicine; and
• Plan and implement risk minimization and mitigation and to assess
the effectiveness of these efforts.19
In many countries, RMPs are a requirement for marketing authorization, and it is
expected that the RMP will be continually modified and updated as the PV work
proceeds and safety data is gathered and assessed.
18 Annex IV, ICH-E2C(R2) Guideline.
19 Guideline on Good Pharmacovigilance Practices (GVP) – Module V, EMA/838713/2001.
10 Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines
Key Principles RMP and risk mitigation applies to all medicines, but for biotherapeutics, including
biosimilars, there is the added emphasis for monitoring because the safety profile
• IFPMA supports pro-active of these medicines is sensitive to seemingly small changes in production processes,
management of potential risks while any problems identified after approval are often related to impacts to the
to further mitigate adverse immune system resulting from the treatment.20 Risk mitigation measures may include
consequences to patients. For educational materials and programs including registries.
effective RMP, an effective
system for identification of
medicines, clear prescribing and Furthermore, considerable effort
recording of the information, is needed in not only engaging
HCPs, patients and their carers in
and good communication to
understanding their role in risk
HCPs, patients and their carers management, but also to explain
are needed. why risk management is needed
and how these safety risks should
be considered in the context of their
treatment.21
To encourage patients and HCPs to report any ADRs through their national reporting
systems, and thereby to help support global safety signal identification and analysis,
some countries and regions have instituted specific monitoring requirements for
newly approved active substances and for all biotherapeutic medicines, including
biosimilars.22
The success of a RMP relies on the possibility to quickly identify potential problems
and therewith on an effective system for identification of medicines, clear prescribing
and recording of the information, and this needs to be well communicated to HCPs,
patients and their carers.
20 Giezen, T. J., et al. (2008). “Safety-Related Regulatory Actions for Biologicals Approved in the United States
and the European Union.” Journal of the American Medical Association (JAMA) 300(16): 1887-1896.
21 Edwards IR, Lindquist M. Understanding and Communicating Key Concepts in Risk Management: What do
we mean by Benefit and Risk? Drug Safety, 2009, 32(6):449-452.
22 For example, the European Union now requires a special symbol for newly approved active substances
and for biologics, including biosimilars, authorised after 1 January 2011 to be included on package. For
further details please see European Commission. Pharmaceuticals: New symbol to identify medicines
undergoing additional monitoring. European Commission, April 19, 2013 [online].
http://europa.eu/rapid/press-release_IP-13-199_en.htm?locale=en
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 11
Roles and Responsibilities
of Stakeholders
The global diversity in the organization of public health systems means that many
countries lack the necessary facilities, expertise and resources for PV.23 Primary
healthcare may not be delivered by medically-trained personnel but rather by
trained non-medical village workers with incomplete understanding of adverse
reactions. Shortages of resources may lead to underdeveloped medical control
systems and lack of laboratory facilities to help diagnose ADRs. Public Health
Programs (PHPs) or Patient Support Programs (PSPs) may exist, based on direct
administration of medicines, either directly controlled by the country, or under the
leadership of an international organization such as WHO or UNICEF. Also in such
programs, patients rarely have direct contact with a physician, as resources are
usually focused on setting up the program.
Where PV systems and PHPs exist alongside each other, this may lead to duplication
of effort and lack of harmonization in terminology, data collection and causality
assessment. Depending on the country, national PV centers may be centralized
or decentralized and function at different levels (district, state or country level).
Whatever the structure, it is important to ensure good coordination, bringing the
relevant expertise together and integrating the PV activity between the different
vertical structures (disease specific PHPs or other systems) in a country or region
together.
For effective PV, global standards and guidelines are needed as well as free exchange
of information regarding ADRs on a local, regional or global level.
Such exchange has been made easier by the standardization of the
minimum criteria for a meaningful adverse reaction report and the
WHO Program for International Drug Monitoring at the
Uppsala Monitoring Centre has been central to this
effort. The objective now is to extend this further
A
and to provide further guidance and direction with
respect to biotherapeutic medicines.
Even the best designed PV system is meaningless
without the contributions of all stakeholders
(regulators, MAHs, HCPs, patients and their carers
and the wider public) (see Figure 4) to provide the
information about a medicine and any potential impact
on safety. The responsibilities of each of the stakeholders in
the risk management cycle have been highlighted below, with special
reference to biotherapeutics.
Figure 4: Key stakeholders
23 WHO. The Safety of Medicines in Public Health Programmes.
Pharmacovigilance an Essential Tool.
12 Similar Biotherapeutic Products: Scientific & Regulatory Considerations
MAHs (Marketing
Authorization Holders)
MAHs are the ‘owner’ of a medicinal product
and as such primarily responsible for
ensuring that the objectives for PV are being
met and that appropriate action can be
taken when needed. In many jurisdictions,
this responsibility is captured in the law.
With respect to biotherapeutics, MAHs
should provide clinical immunology and
analytical support to HCPs and patients to
help them to identify and manage related
individual circumstances, the regulator and
ADRs. Regulators
The regulators have a dual role in PV health authority should encourage the HCPs
activities. On the one hand, they supervise to carefully consider and document the
MAHs the compliance of applicants with their PV substitution to ensure accurate traceability.
activities. Moreover, guidance regarding substitution
MAHs, usually through a qualified
between products, including between
person for PV, are responsible for: On the other hand, they play a role in biosimilars and their reference products,
• Continuous monitoring of PV facilitating PV activities in their territory should be provided to ensure that these
data and scientific evaluation of (e.g. by facilitating reporting of ADRs or products are not used interchangeably
all information on the risks of the by creating databases that allow pooling without evidence supporting a lack of
m edicinal product. of data to facilitate analysis). They can impact on patient safety or efficacy.
• Submission of accurate and verifiable also play a role in proactive safety reviews
data on ADRs to the competent and data capture that can be organized An efficient and direct way to provide HCPs
authority. for cohort event monitoring, linked to a with essential information is to include such
• Effective communication with the particular healthcare investment or initiative. information and guidance in the labelling
competent authority on any Such examples are evident for healthcare of the medicine. More generally, common
information that may impact the programs initiated by WHO and other non- communication methods and templates
benefit/risk balance. governmental organizations and charities.24 could facilitate more effective recording and
• Update of the product information to reporting of adverse events and proactive
reflect all scientific knowledge and For biotherapeutics, regulators should also risk management.
communication of relevant safety provide guidance and support to HCPs and
information to HCPs and patients. patients to help them to identify and report
ADRs, advising specifically on the need Regulators
for product-specific identifiers, including Regulators will organize PV inspections
batch numbers. With respect to process t o ensure that:
changes for biotherapeutics, the regulators • The MAH has everything in place
closely assess these changes for impact on that is needed to meet the PV
safety and efficacy and monitor the results r equirements.
accordingly. Because substitution of one • To identify and address
biotherapeutic medicine for another in the non-compliance and take
course of a patient’s treatment requires enforcement action when necessary.
careful consideration of the patient’s
24For further details on cohort event monitoring and examples, please refer to:
http://www.who.int/hiv/topics/pharmacovigilance/4_pharmacovigilance_cem.pdf
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 13
HCPs (Healthcare Patients and their carers Key Principles
Professionals) Patients primarily have the responsibility to • Even though the clinical effect
Spontaneous reporting systems are the comply with the treatment schedules and
of certain products may be
most common mechanism by which safety recommendations in the label and to be
similar, healthcare professionals
reporting occurs, and these systems rely aware of important risks. Although much
should be educated on the
heavily on the direct contributions of all of the focus for ADR reporting has been
necessity for using
stakeholders who have been involved in the centered on the regulatory authorities, the
distinguishable names when
prescription, delivery and use of a medicine manufacturers responsible for the medicines
prescribing biotherapeutic
by a patient. This includes physicians, themselves and the reporting healthcare
medicines. This practice will help
pharmacists or other healthcare workers. practitioner, PV systems are opening up to
maintain the role of the physician
Their role is to ensure that the patient is more direct input from patients themselves
in selecting a particular therapy
sufficiently informed and motivated to as well as other representative bodies. A
for the patient and provide
report any untoward effects they may good understanding by patients of the
clarity for the pharmacist about
experience. They also have a crucial role potential benefits and risks of a medicine is
what medicine was prescribed.
in ensuring traceability of the prescribed likely to have a positive effect on reporting
product by ensuring that all necessary of ADRs and compliance with suggested risk • Confusion about the
information on the product prescribed and minimization activities (see Table 1). physician’s intended treatment
dispensed is included in the patient file, choice may lead to automatic
which can be accessed for verification e.g. in substitution and inaccurate
case of a reported ADR. For biotherapeutics, attribution of ADRs as the
these roles and responsibilities remain the prescribing physician may not
same, nevertheless further education and be aware which medicine the
engagement may be helpful in preparing all patient received.
stakeholders to identify and manage related • Currently, there is no scientific
ADRs. basis to conclude that greater or
lesser rigor in the collection of PV
Availability of batch numbers for reported suspected data for biosimilars is required
biopharmaceuticals stratified by type of reporter when compared with originator
Reporter type FAERS (n=487,065) EV (n=356,293) products. Ensuring that all
biotechnology manufacturers,
Total number Drugs with batch Total number Drugs with batch
of drugsa number available of drugs number available adhere to global standards
[n(%)] [n(%)] for manufacturing and PV
Physician 112,770 15,026 (13.3) 94,928 6,667 (7.0) (WHO, ICH, CIOMS,) will protect
Pharmacist 12,971 2,984 (23.0) 9,999 1,896 (19.0) patient safety and maintain the
Other healthcare
professional 64,235 9,087 (14.1) 46,765 5,366 (11.5) quality of existing PV practices.
Consumer 198,282 76,006 (36.3) 117,411 47,800 (40.7) Therefore, each MAH of each
Lawyer 1,489 10 (0.7) 1,242 5 (0.4)
biological product must have an
a For a total of 97,318 biopharmaceuticals in the FAERS and 85,948 in EV, the reporter type was not established PV system to ensure
unique or unavailable. EV Eudra Vigilance, FAERS FDA Adverse Event Reporting System
comprehensive monitoring of
Table 1: Availability of batch numbers for reported suspected biopharmaceuticals the product.26
stratified by type of reporter 25
25 Vermeer, N., et al. (2013). “Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: A Cross-Sectional
Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance Databases”. Drug Safety 36(8): 617-625.
26 WHO http://www.who.int/biologicals/en/; International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use http://www.ich.org/; Council for International Organizations of
Medical Sciences http://www.cioms.ch/
14 Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines
Global Signal Detection
Global pharmaceutical companies aim to develop and make their products available to
patients worldwide. This means that ADRs will be reported in principle from many countries
all over the world. In addition, ADRs can be reported by HCPs, regulatory authorities, patients
or anyone else who becomes aware of an untoward effect to a certain medicine. To allow
correct and timely reporting and analysis of this large variety of data, pharmaceutical
companies have set up extensive PV systems. A schematic outline of the path followed by an
ADR starting at the reporter and ending with the actual inclusion in the database is given in
Figure 3.
Minimum criteria have been defined for information that needs to be available in order
to have a meaningful case report. Lack of any of these elements means that the case is
incomplete. It is the responsibility of the MAH to put every effort into collecting the missing
data. However, in practice, the success rate of such follow-up queries is low, while also privacy
considerations have to be taken into account.
The 4 essential elements for an ADR:
(1) Identifiable reporter
(2) Identifiable patient
(3) Adverse reaction
(4) Suspected product
Both the MAH and the NRA have the task to collect sufficient information to ensure that
reports are authentic, accurate, as complete as possible and non-duplicative. Furthermore,
a high number of drug-specific ADRs in an adverse reactions database have been shown to
increase the power for detecting safety signals.27 From that perspective, it is beneficial to be
able to share and exchange information on adverse reaction reports. Global standards for
essential elements in reporting processes and definitions would facilitate the use of global
databases for collating and searching data as well as for testing hypotheses once a signal has
been detected. Such standards, specifically in relation to the 4 essential elements, can also
facilitate the elimination of duplicates (based on identifiable reporter and patient) and avoid
misclassifications (e.g. due to imputation of the name of the suspected product when the
reported name does not unequivocally identify the individual product). Overall, consistent
global processes and use of well-defined standards will increase the quality of the data.
27 Hammon IW, Gibbs TG, Seifert HA, Rich DS. Database Size and Power to Detect Safety Signals in
Pharmacovigilance. Expert Opin Drug Saf 2007;6:713-21.
Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines 15
Summary
Biotherapeutic medicines, including biosimilars, have brought considerable benefits to
patients around the world. New biotherapeutic medicines and more alternatives for supply
will bring further value to patients and to healthcare systems. However, because of the
complexity of biotherapeutic medicines and their unique method of manufacture, a strong
PV system is needed to ensure that value is maintained and patient safety remains at the
center of our efforts.
Effective PV for biotherapeutics, particularly as multiple sources of biotherapeutics emerge
globally, requires that we establish product-level traceability. Some of this will be made
possible by advances in non-proprietary identification. However, much of this effort relies
upon the effectiveness of PV systems and the practices of safety reporting amongst not only
regulators and manufacturers, but critically amongst HCPs, patients and the wider public.
Countries generally have some form of PV system in place, and this has developed in the
context of the healthcare setting and needs of that country. However, PV is a global effort,
and we support the WHO in its efforts to help countries to further develop their PV systems
and practices to reach a common standard and to encourage and support global safety
reporting and analysis for the benefit of all patients.
Characteristics of robust PV systems
• Easy to use (reporting forms, procedures for submission and collection of reports)
• Allows reporting by patients and healthcare providers
• Well structured to facilitate analysis
• Standardized procedures and definitions (e.g. what is a reportable event, follow-up
and processing of case reports)
• Allows analysis on product class level (e.g. epoetin) and on individual product level
(by manufacturer or MAH)
• Procedures for analysis of aggregated information
• Good communication practices
• Training
Collaboration is key
Greater engagement in and support for PV practices are needed to empower all stakeholders
to help deliver effective safety reporting on a global basis. Good practices exist in many
countries, but in too many settings, patients, HCPs and other stakeholders do not understand
the role that they should play or feel concerned that they will not be well received by the
authorities if they raise safety concerns. The EMA recognizes this important measure, and it
will soon be publishing its first “Good Vigilance Practice” Module (XI) on public participation
in PV. This is a trend that must become global if we are to ensure that the effective PV systems
we establish, have the critical input of safety information provided by all stakeholders – our
critical partners for PV.
16 Good Pharmacovigilance Principles and Considerations for Biotherapeutic Medicines
Glossary
Adverse (Drug) Reaction (ADR): A response which is noxious and Immunogenicity: The ability of a substance to trigger an unwanted or
unintended, and which occurs at doses normally used in humans for the unanticipated immune response or reaction.34
prophylaxis, diagnosis, or therapy of disease, or for the modification of Immune System: A system that protects the body against foreign
physiological function. (WHO, 1972). substances and pathogens, including virus and bacteria.35
An ADR, contrary to an adverse event, is characterized by the suspicion Marketing Authorization Holder (MAH): The person or company
of a causal relationship between the drug and the occurrence, i.e. judged in whose name the marketing authorization has been granted. This
as being at least possibly related to treatment by the reporting or a party is responsible for all aspects of the product, including quality
reviewing health professional.28
and compliance with the conditions of marketing authorization. The
Adverse Event (AE): Any untoward medical occurrence that may present authorization holder must be subject to legislation in the country
during treatment with a pharmaceutical product but which does not that issued the marketing authorization, which normally means being
necessarily have a causal relationship with this treatment.29 physically located in the country.36
Biotherapeutic Medicines: Medicines whose active ingredients are or National Regulatory Agency (NRA): Public authority or government
are derived from proteins (such as growth hormone, insulin, antibodies) agency responsible for exercising autonomous authority over some area
and other substances produced by living organisms (such as cells, of human activity in a regulatory or supervisory capacity.37
viruses and bacteria). They are larger and more complex than chemically Originator Product: A medicine which has been licensed by the national
synthesized drugs and their characteristics and properties are typically regulatory authorities on the basis of a full registration dossier; i.e. the
dependent on the manufacturing process itself.30
approved indication(s) for use were granted on the basis of full quality,
Drug Substance: An active ingredient that is intended to furnish efficacy and safety data.38
pharmacological activity or other direct effect in the diagnosis, cure, Pharmacodynamics: Is the exploration of what the Medicinal Product
mitigation, treatment, or prevention of disease or to affect the structure or does to the body.39
any function of the human body, does not include intermediates used in
the synthesis of such ingredient (21 CFR 314.3(b)). The term drug substance Pharmacoepidemiology: Study of the use and effects of drugs in large
can also be used to refer to a physical mixture of two or more drug populations.40
substances used to produce a fixed-combination drug product.31 Pharmacovigilance (PV): The science and activities relating to the
Disproportionality Analysis: Screening of Individual Case Safety Report detection, assessment, understanding and prevention of adverse effects
(ICSR) databases for reporting rates which are higher than expected. or any other drug-related problem.41
For drug-ADR pairs, common measures of disproportionality are the Signal: Reported information on a possible causal relationship between
Proportional Reporting Ratio (PRR), the Reporting Odds Ratio (ROR), The an adverse event and a drug, the relationship being unknown or
Information Component (IC), and the Empirical Bayes Geometrical Mean incompletely documented previously. Usually more than a single report
(EBGM). There are also disproportionality measures for drug-drug-ADR is required to generate a signal, depending upon the seriousness of the
triplets, such as Omega (Ω).32
event and the quality of the information. The publication of a signal
Epidemiology: The science concerned with the study of the factors usually implies the need for some kind of review or action.42
determining and influencing the frequency and distribution of disease, Similar Biotherapeutic Product (SBP) or Biosimilar: A biotherapeutic
injury and other health-related events and their causes in a defined product which is similar in terms of quality, safety and efficacy to an
human population for the purpose of establishing programs to prevent already licensed reference biotherapeutic product. Note: The WHO prefers
and control their development and spread.33
to use the term SBP. 43
28 The Uppsala Monitoring Center (2013) Glossary of Terms Used in Pharmacovigilance. 36 WHO (1998) Marketing Authorization of Pharmaceutical Products with Special Reference
The Uppsala Monitoring Center, September 29, 2014 [online]. to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities – Regulatory
http://www.who-umc.org/graphics/27400.pdf Support Series No. 005. World Health Organization, February 23, 2015 [online]. http://apps.
29 Idem. who.int/medicinedocs/en/d/Js2273e/10.html
37
30 WHO (2009) Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). FDA (2015) Glossary of Terms. US Food and Drug Administration, January 5, 2015 [online].
World Health Organization, September 29, 2014 [online]. http://www.who.int/biologicals/ http://www.fda.gov/forpatients/clinicaltrials/ucm410359.htm
areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf?ua=1 38 WHO (2009) Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). World
31 FDA (2010) Guidance for Indutry – Drug Substance Chemistry, Manufacturing, and Health Organization, September 29, 2014 [online]. http://www.who.int/biologicals/areas/
Controls Information. US Food and Drug Administartion, December 12, 2014 [online] biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf?ua=1
http://www.fda.gov/downloads/animalveterinary/guidancecomplianceenforcement/ 39 EMA (2010) EU Clinical Trials Register. European Medicines Agency, January 6, 2015 [online].
guidanceforindustry/ucm052498.pdf https://www.clinicaltrialsregister.eu/doc/EU_Clinical_Trials_Register_Glossary.pdf
32 The Uppsala Monitoring Center (2013) Glossary of Terms Used in Pharmacovigilance. 40 The Uppsala Monitoring Center (2013) Glossary of Terms Used in Pharmacovigilance.
The Uppsala Monitoring Center, January 5, 2015 [online]. January 5, 2015 [online]. http://www.who-umc.org/graphics/27400.pdf
http://www.who-umc.org/graphics/27400.pdf 41 WHO (2014) Essential Medicines and Health Products: Pharmacovigilance. World Health
33 Idem. Organization, February 3, 2014 [online]. http://www.who.int/medicines/areas/quality_safety/
34 WHO (2009) Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). safety_efficacy/pharmvigi/en/
World Health Organization, September 29, 2014 [online]. http://www.who.int/biologicals/ 42The Uppsala Monitoring Center (2013) Glossary of Terms Used in Pharmacovigilance.
areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf?ua=1 September 29, 2014 [online]. http://www.who-umc.org/graphics/27400.pdf
35 WHO (2004) The Health Academy Avoiding Tuberculosis – Self Study Program on 43WHO (2009) Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). World
Tuberculosis. World Health Organization, January 16, 2015 [online]. Health Organization, September 29, 2014 [online]. http://www.who.int/biologicals/areas/
http://www.who.int/healthacademy/WHO_TB.pdf?ua=1 biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf?ua=1
About IFPMA:
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