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International Clinical Trials

Safety Signals

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.


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.


  1. World Health Organization, The importance of pharmacovigilance: safety monitoring of medicinal products, 2002
  2. World Health Organization, Technical Report Series No 498: International Drug Monitoring: The Role of National Centres, 1972, available at: Accessed: 28 June 2012
  3. Food and Drug Administration Amendments Act (FDAAA) of 2007. Available at: Legislation/FederalFoodDrugandCosmeticActFDCAct/ Signifi cantAmendmentstotheFDCAct/ FoodandDrugAdministrationAmendmentsActof2007/default.htm. Accessed: 28 June 2012
  4. European Medicines Agency, Good pharmacovigilance practices. Available at: regulation/document_listing/document_listing_000345. jsp&mid=WC0b01ac05804fcdb1. Accessed: 28 June, 2012
  5. Guideline on good pharmacovigilance practices (GVP) – Module VI; EMA/873138/2011. Available at: document_library/Scientific_guideline/2012/06/WC500129135.pdf. Accessed: 10 August, 2012
  6. Draft Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines. Available at: GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ ucm074850.htm#9

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Peter Bottini has an accomplished career of more than 33 years in strategic planning, clinical research and pharmacovigilance for both brand and generics companies. He has held various leadership positions, including Head of North American Product Safety for an international generics company. Peter has participated in many risk management programmes, and was a founding member in the US iPLEDGE (isotretinoin) pregnancy REMS programme. Peter’s writing has appeared extensively in publications and abstracts. He received his PharmD from the University of Missouri, Kansas City School of Pharmacy, and was awarded a Fellowship with the American College of Clinical Pharmacology.
Peter Bottini
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