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International Clinical Trials
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The approach to pharmacovigilance in an expanding global environment is
evolving, taking in data processing and analysis, alongside
postmarketing safety reporting.
Pharmacovigilance is a complex and continuously evolving discipline that
involves coordinated interaction between patients, healthcare
professionals, pharmaceutical companies and regulatory authorities. The
goal of pharmacovigilance is to detect, assess, understand and prevent
adverse events associated with medicinal products, with the aim of
enhancing patient care and safety. While this goal remains constant, the
methods, resources and regulations that are established to help reach
this goal are continuously being updated and optimised (1).
The term ‘pharmacovigilance’ was originally coined in 1972 to describe a
“national system for the vigilance of the unintended and toxic effects
of medicines” (2). Early strategies were led by pharmaceutical companies
and restricted by the limited pool of data gathered from the relatively
small and narrowly defined clinical trial population. Over the past few
decades, and under the watchful guidance of regulatory agencies, the
process has evolved to become more proactive in the monitoring,
assessment and reporting of drug-related adverse events.
During this time, the pharmaceutical industry itself also went through a
period of transition. In the not-so-distant past, fully integrated
pharmaceutical companies internally managed all aspects of drug
development, including manufacturing, clinical research and marketing.
As a result of increasing economic and productivity pressures, expansion
of the generic marketplace, and globalisation of manufacturing and
clinical research, many pharmaceutical companies have partnered with
specialised contract organisations to supplement their core service
offerings, including the outsourcing of manufacturing and clinical trial
execution. More recently, the clinical and regulatory expertise of CROs
has also been utilised by pharmaceutical companies for the initiation
and implementation of pharmacovigilance processes and procedures
throughout the lifecycle of their products. These contracting
collaborations for fulfi lling pharmacovigilance obligations have been
recognised in the guidelines set forth by regulatory authorities, and
require only that such arrangements are disclosed.
Global Pharmacovigilance
Although pharmacovigilance is a concept that is recognised globally,
specific regulations are mandated by various country and region-specific
authorities. The US regulatory framework has evolved since the
implementation of the amended Federal Food, Drug, and Cosmetic Act in
1962, which introduced the terms ‘safe’ and ‘effective’ as key, concrete
concepts. More recently, the passage by Congress of the Food and Drug
Administration Amendments Act of 2007, which was aimed at enhancing the
safety of medical products, increased the oversight and authority of the
FDA over investigational and marketed drugs, and created new standards
for integrating risk evaluation and mitigation strategies into the
review of new drugs and post-marketing activities (3). Similarly, the EU
is currently at a pivotal point in pharmacovigilance history, with the
implementation of legislation that calls for a greater transparency in
the collection and reporting of adverse events (4).
It is important for pharmaceutical companies and CROs alike to
understand the breadth and depth of international standards, as many
pharmaceutical agents are marketed in multiple countries, and therefore
not bound by only one set of regulatory requirements. The globalisation
of drug manufacturing and distribution requires an efficient,
comprehensive programme for maintaining international pharmacovigilance
standards. For example, international rules require that suspected
postmarketing, serious, unlisted reactions are reported within 15 days.
However, even this seemingly standardised process is subject to
interpretation by regulatory authorities, resulting in confusion about
the start date for this process (for example, day zero versus day one).
Moreover, with the implementation of clinical research activities and
pharmacovigilance initiatives in emerging growth markets (EGM) that fall
outside of FDA and EMA authority, there is an urgent need to understand
the critical importance of the regulated surveillance and assessment of
drug safety, to ensure regulatory compliance and enhance safety
throughout the life cycle of the product. While great strides have been
made in emphasising the importance of pharmacovigilance, these concepts
need to be translated into real-world operations a process that takes
substantial monetary, resource and time commitments.
Pharmaceutical companies are required to keep up with the systems and
processes put into place by regulatory agencies in various countries and
regions across the globe in which their drugs are available. This is
true of companies that market brand-name products, as well as those that
focus on generic equivalents. If pharmacovigilance is not part of a
company’s core offerings, they can turn to a CRO experienced in
pharmacovigilance to establish and implement standardised, yet fl
exible, systems and processes to monitor the regulatory landscape and
meet the demands required by various regulatory agencies throughout the
life cycle of their products.
Pharmacovigilance Process from a CRO Perspective
Risk management and signal detection are critical components of
successful drug development. Although global regulations are diverse,
there are common components at the core of any effective
pharmacovigilance system, including the systematic integration of
diverse information into a central database; identification and
assessment of potentially important safety signals; and communication of
a recommended course of action in a timely manner, with the ultimate
goal in mind of maximising benefi t and minimising risk to patients.
To attain good pharmacovigilance practices, standard processes for
information flow should be implemented, as well as the identification of
key players and responsibilities at each step of the process. A strong
platform will better allow for the flexibility needed to address
specific considerations across multiple drugs and therapeutic settings.
As with any efficient and effective process, seamless and open
communication between all departments is a critical success factor.
The niche for CRO-based pharmacovigilance practices has been established
in the global regulatory environment. However, it is the specific
expertise and implementation of this process fl ow that defines the
success of one pharmacovigilance system over another. This section will
explore important success factors in the design, implementation and
ongoing optimisation of effective pharmacovigilance practices.
Data Management
A functional, powerful database that offers intrinsic flexibility to be
updated and configured – as specific regulatory and product needs
dictate – is the cornerstone of an effective pharmacovigilance
programme. The database should have all of the components required for
case assessment, accurate search metrics, and electronic-reporting
capabilities that meet regulatory requirements. For example, to comply
with the updated EU pharmacovigilance regulations established in Module
VI of the Guidelines on Good Pharmacovigilance Practices, the responsibe
party should ensure compliance with the necessary quality standards at
every stage of case documentation such as data collection, data
transfer, data management, data coding and so on (5).
As with any information associated with health records where patients
are at risk of being identified through the specific information
collected, data security is of utmost importance to ensure that patient
privacy is maintained. Multiple, redundant technical and functional
controls should be implemented to protect pharmacovigilance data from
unauthorised access, use, loss and release. These parameters are further
highlighted by regulations which require that:
- Access to pharmacovigilance databases is restricted to authorised personnel
- Traceability of all data entered or modified be maintained
- Systems undergo regular validation to ensure accuracy, reliability and anonymity
These criteria only represent a few examples of the full spectrum of
capabilities that a pharmacovigilance database must offer. Companies
embarking on start-up pharmacovigilance efforts quickly realise that the
design, installation and maintenance of such a system are costly and
time-consuming, and may wish to consider utilising the expertise of a
third party to effectively and efficiently perform these functions.
Furthermore, technology is an important, but not singular, aspect of
data management. The database is only as good as the subject-matter
expertise that goes into its design and functionality. This expertise
represents a dichotomy between two unique, but critically important
skill sets: information technology (IT) and medical proficiency. The IT
specialist should be an authority in the field, with specific experience
in pharmacovigilance database set-up and maintenance, with a core
understanding that the functionality of the database is an ever-moving
target, based on the critical assessment of specific needs by the
medical expert. This medical expert should be aware of the nuances
between potential safety signals across a wide variety of pharmaceutical
agents, therapeutic areas, and population at risk, all of which is
information that will go into the development of the case definition and
help determine how the database search should be optimised to identify a
potential safety signal. Communication between the IT specialist and
the medical expert is required to ensure that the database fulfils all
needs from a good pharmacovigilance practice perspective.
Data Processing and Analysis
As discussed, information that has been entered into a company’s safety
database undergoes both qualitative and quantitative analyses by medical
safety department professionals to identify possible safety signals.
Medical expertise is a critical component of the qualitative analysis of
a case report that is being investigated for a potential drug-related
adverse event. This expertise includes not only an in-depth knowledge of
the drug, pharmacokinetics, and known safety profile, but also an
integrated understanding of the disease, epidemiological factors, and
comorbidities of the patient, each of which may influence the efficacy
and safety of the given drug.
The pharmacovigilance medical expert is responsible for making a
value-based judgment as to whether the reported event is a safety
signal, where a potential causal relationship can be identified between a
previously unknown or incompletely documented adverse event. More than
one report is typically required to generate and corroborate a safety
signal, especially since spontaneously reported events are not uniform
in severity and the amount and quality of information that is documented
in each case. Therefore, when available, individual case reports are
collected from the database, and aggregate data are used to make a value
judgment about the relevance of the potential safety signal to the
pharmaceutical agent. Although the database allows for this aggregation
of data to be performed as efficiently as possible, the process of
evaluating a safety signal can be akin to finding a needle in a
haystack, and efforts to identify methods for increasing the efficiency
of this process continue. In the meantime, precautions and best
practices should be in place and regularly assessed for optimisation to
identify the risks in the shortest possible time so that harm can be
avoided or minimised.
All relevant safety information should be synthesised – for example,
into a position paper – that provides value-based guidance for effective
risk management and regulatory reporting. The pharmacovigilance opinion
should not be a dictum, but reviewed with the corporation in an
interdisciplinary setting to determine the best approach for regulatory
notification. Guidance for regulatory action is proposed according to
the seriousness of the issue and the individual benefit/risk assessment.
For example, if the safety signal is deemed to be a serious, previously
unknown concern, the corporation, through a step-wise approach, may
recommend that action be immediate, such as the requirement for a
post-marketing study; a proposed label change to take into account this
newly defined risk; the development and dissemination of a ‘Dear
Prescriber’ letter and so forth. This is in contrast to less-serious
signals that may be monitored and ultimately incorporated into the
safetyupdate report that is provided to regulatory authorities on a
periodic basis.
In the case of generic drugs, safety signals are managed in a variety of
ways worldwide, depending upon rules set forth by individual regulatory
agencies. Actionable recommendations, such as a label change, are
either submitted to the regulatory agencies for review and ultimate
action (as is the case in the US). In contrast, corporations in the EU
can enact changes to their own generic labels at a local level in order
to notify prescribers of the particular safety concern. This is one of
many examples where a detailed knowledge of pharmacovigilance
requirements is required to maintain in compliance with regulatory
authorities.
Postmarketing Safety Reporting
Guidance from the FDA, as well other regulatory agencies, is available
regarding postmarketing safety reporting requirements for marketed
medicinal products. Types of reports that are required include: 15-day
reports of serious, unexpected adverse events; periodic reports for each
approved application (due quarterly for the first three years after US
approval and annually thereafter); and follow-up reports (6).
In the US, when a serious, unexpected adverse event is reported,
licensed manufacturers have 15 days to verify the validity of the case
information, to process and review the information, and to report the
information on behalf of the sponsor to the appropriate regulatory
agency. A serious report must have one or more of the following
outcomes: death, life-threatening adverse experience; initial or
prolonged hospitalisation; significant disability; or congenital anomaly
(6). Best practices should ensure that this process is performed as
efficiently and as accurately as possible. Most safety reporting is done
electronically, providing the advantage of allowing simultaneous
transmission of safety data to multiple regulatory agencies. However,
time, resource and process allocations need to be made for reporting
that is not able to be conducted electronically. A conservative,
standardised approach to this requirement will ensure that the process
adheres to the highest standards, keeping the pharmaceutical company
compliant and good-standing with the overseeing regulatory authority. A
follow-up report provides information about an adverse experience that
has been previously reported by a 15-day report. This must be submitted
within 15 days of receipt of new information.
The 15-day reporting process involves the collection and collation of
all available, relevant information from a variety of sources, including
clinical trial databases, literature searches, patient registries,
epidemiological studies and so on. Of note, with the recent passing of
the legislation in the EU on roles and responsibilities for
adverse-event reporting and tracking, the EMA is taking on ownership of
the literature searches that previously fell on the group responsible
for pharmacovigilance surveillance. While this represents a positive
step in sharing responsibilities and centralising safety data, it would
be remiss for a CRO to neglect establishing and maintaining standard
operating procedures for this important role, especially in situations
where the organisation has the potential to conduct research within
areas that fall outside of EMA guidance.
Integrated Collaboration
Providing the full spectrum of pharmacovigilance services requires a
fully integrated support team to handle the medical, technical and
quality-assurance aspects of the process. The Quality Assurance
department follows Good Manufacturing Practice to ensure that the
product is made according to quality standards. The IT department can
develop the programming to turn functional requests from the medical
experts into reality, as well as maintain and update the database, as
necessary. The pharmacovigilance department maintains an awareness of
safety issues in the evolving pharmacovigilance landscape, and
communicates the laws, regulations, and guidelines from these regulatory
agencies to the members of the internal pharmacovigilance group, while
ensuring that the internal processes meet the expectations of global
regulatory agencies so that the organisation – and by extension, the
pharmaceutical company – remains in compliance.
Future Perspectives
Pharmacovigilance has come a long way in the past few decades. However,
there is room and impetus for improvement, especially given the
technologically-driven society in which we live and work. Access to
external safety databases to confirm a suspicious finding will be
critical to early detection of safety concerns. Further optimisation and
advancement of databases from systems that collect, aggregate, and
report data to systems that analyse data in the broader context of the
clinical and drug-utilisation landscape will help to enhance the
process. By turning this subjective process into one that is
mathematically based, it will minimise the human error element of
missing important information that may be hidden in the stacks of data.
The goal would be for the database to be programmed to account for a
relevant set of variables (for example, the number of units sold over
time) and normalise the process of signal detection against theoretical
risk. Medical expertise would, of course, be required to guide the
analysis and to correlate and validate findings, but the greater
implementation of software would make the process not only more
efficient, but also increase the reproducibility of the process – the
foundation of the scientific process.
Conclusion
Effective pharmacovigilance practices require that the responsible
organisation maintains a finger on the pulse of the evolving landscape,
including updates on new legislation and how revised regulations may
impact processes and procedures. The coordinated efforts of the
departments involved in pharmacovigilance ensure that important safety
signals are identified and communicated efficiently so that harm can be
minimised to the greatest extent possible.
References
- World Health Organization, The importance of pharmacovigilance: safety monitoring of medicinal products, 2002
- World Health Organization, Technical Report Series No 498:
International Drug Monitoring: The Role of National Centres, 1972,
available at: http://who-umc.org/graphics/24756.pdf. Accessed: 28 June
2012
- Food and Drug Administration Amendments Act (FDAAA) of 2007.
Available at: www.fda.gov/RegulatoryInformation/
Legislation/FederalFoodDrugandCosmeticActFDCAct/ Signifi
cantAmendmentstotheFDCAct/
FoodandDrugAdministrationAmendmentsActof2007/default.htm. Accessed: 28
June 2012
- European Medicines Agency, Good pharmacovigilance practices.
Available at: www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/document_listing/document_listing_000345.
jsp&mid=WC0b01ac05804fcdb1. Accessed: 28 June, 2012
- Guideline on good pharmacovigilance practices (GVP) – Module VI;
EMA/873138/2011. Available at: www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2012/06/WC500129135.pdf. Accessed:
10 August, 2012
- Draft Guidance for Industry: Postmarketing Safety Reporting for
Human Drug and Biological Products Including Vaccines. Available at:
www.fda.gov/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/
ucm074850.htm#9
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