Brian Edwards

Teaching Pharmacovigilance: the WHO-ISoP Core Elements of a Comprehensive Modular Curriculum

The importance of pharmacovigilance (PV) for safe medicines and their safe use has increasingly been recognised during the last few years [1]. PV has been subject of intense research and regulation. In particular, it has earned more and more importance and attention in low-resource countries. This is largely due to the globalisation of trade and the availability of new, highly effective but potentially harmful chemical medicinal products in those parts of the world where traditional treatments, in particular herbal or other complementary remedies, used to prevail. A plethora of publications, guidelines and information about newly observed or further investigated adverse drug reactions (ADRs) from all over the world creates a growing burden for people working with medicines or patients to keep abreast of this development. Largely due to the global availability of information through the Internet, patients are nowadays more and more critical and often concerned about, or even frightened of, potential ADRs of their medicines. This poses an additional demand on the up-todate capacities of their doctors and other healthcare professionals (HCPs). A particular challenge is the multidisciplinary character of PV which requires know-how in topics as different as molecular mechanisms of ADRs, clinical medicine, pharmacoepidemiology, information technology, pharmaceutical manufacturing, legal aspects, public health situations on various levels, and traditions in The views expressed in this article reflect a consensus reached between the personal views of all authors. They do not necessarily reflect the views of the authors’ employers or any institutions the authors are otherwise affiliated to.

Risk Communication and the Pharmaceutical Industry

Risk communication is central to the risk management strategy of a pharmaceutical company. Pharmaceutical companies primarily communicate risk through labelling tools such as the Summary of Product Characteristics (SmPC), package insert, patient information leaflet (PIL) and the carton, which are currently regulated based on templates such as those of the EU. Recent research raises concern about how effective the SmPC is alone in communicating risk. There is some evidence that carton design can influence risk comprehension. Processes to check new trade names cannot be confused with existing names is a simple measure to mitigate one form of risk. Given the central role and the vast amount of resource that is consumed, it is surprising there has not been extensive original research to see whether product information such as the SmPC is a good tool for communicating risk. Recently, EU agencies have assessed the communication value of the PIL and revised the template and guidelines. However, no evaluation of user testing has been conducted at European level since the introduction of these new requirements. As regards ‘Dear Healthcare Professional Communications’, there is inconsistent evidence about their ability to change patient and physician behaviour. There is a dearth of evidence about what sort of communications materials are the most effective under which circumstances.The use of templates restricts the flexibility of companies to adapt their risk messages to their targets. Effective communication requires understanding how different audiences perceive the message and what the funda-mental drivers are for altering patient and prescriber behaviour to be safer. This requires careful consideration of the relationship between risk communication, perception and management. However, the focus of a company’s risk communication plan is normally on the International Conference on Harmonisation (ICH) regions and their regulations. Although the same regulatory tools are used globally, we are not aware of any research into their effectiveness outside the ICH regions.What listed companies can communicate about benefits and risks is strongly influenced by the obligations of companies to the market and investors. There needs to be internal coordination for simultaneous release. Internal communications about significant issues should be restricted to those who know how to manage the risk of insider dealing from internal communications that may later be made public.Unfortunately, there is evidence that some companies do not have a cohesive strategy for communicating risk which should take into account all forms of promotional material and company-sponsored information sources on the Internet.A pharmaceutical company is not the only stakeholder responsible for communicating risks on their products. However, the relative roles and responsibilities of all relevant stakeholders are not defined and are often un-clear. This means it is difficult to evaluate whether a company’s actions might be duplicative or inefficient. We recommend that companies have a dedicated communications group whose role is to coordinate the company’s communications strategy mapped to objectives that have been agreed with key stakeholders apart from just regulatory agencies. This same group can assess effectiveness of the communications, monitor audience reaction and adjust the communication strategy accordingly.

The ISoP CommSIG for Improving Medicinal Product Risk Communication: A New Special Interest Group of the International Society of Pharmacovigilance

Communicating to patients and healthcare providers about the risks of harm with medicines and how to use medicines safely is vital to pharmacovigilance for fulfilling its objectives—there is no or little risk avoidance/mitigation or patient safety without risk communication. Communication about risk characteristics and factors should also enable patients and healthcare providers to make informed therapeutic choices. This requires discussing risks of medicines in the context of their benefits as well as the risks of deciding against medication. Usually medicines are meant to benefit the individuals taking them. In the area of infectious diseases, however, vaccines are aimed at protecting the vaccinee and also, through repressing or eradicating the disease, protecting vulnerable individuals who cannot be vaccinated. For a considerable time, guidance documents on communications have been available from international pharmacovigilance specialists [1–4] and some regulatory authorities (e.g. [5–8]). However, application of these documents in everyday pharmacovigilance has been a challenge. An issue of Drug Safety not long ago, dedicated to the theme of risk communication, discussed barriers to implementation and proposals for improving communication practices from worldwide experience [9–17]. There is much more research on medical information, communications and risk perception available, but every time a major safety concern arises with a medicine, designing a communication strategy and materials for avoiding and mitigating risks is perceived as a complex new challenge by both industry and regulatory authorities, and either the available evidence from the communication sciences is not fully applied or specific research to guide them is lacking. With rapidly changing communication tools, landscape and behaviour, it is not easy for research to catch up. However, communicating must be a paramount consideration whenever new safety information becomes available. Independently from which communication modalities are chosen, the content must be useful and understandable for those that should benefit from it (patients and healthcare providers), but also for other possible recipients like the general public and those in mediating roles such as drug information pharmacists and journalists. This On behalf of the ISoP CommSIG.

Intentional Rechallenge: Does the Benefit Outweigh the Risk?

Rechallenge is defined as the readministration of a medication suspected of being a possible cause of an adverse reaction and which has been discontinued as result. It may be unintentional when the appearance of a reaction was initially not attributed to the medication. A rechallenge may be intentional when a prescriber decides that the benefit of rechallenge will outweigh its risk. When considering intentional rechallenge, one should take into account the benefit/risk balance of the suspected causative medication, and the benefit/risk balance of the best available alternative treatment or no treatment. Clinical knowledge is essential in benefit/risk assessment but there is currently no suitable tool to guide the decision on rechallenge. This article aims to propose points to consider in the creation of reaction-specific algorithms for risk assessment and management in the case of drug rechallenge.

Embedding ‘Speaking Up’ into Systems for Safe Healthcare Product Development and Marketing Surveillance

Robust, active cooperation, and effective, open communication between all stakeholders is essential for ensuring regulatory compliance and healthcare product safety; avoiding the necessity for whistle-blowing; and, most essentially, meeting the transparency requirements of public trust.The focus here is on what can be done within a healthcare product organization (HPO) to achieve actionable, sustainable policies and practices such as leadership, management, and supervision role-modelling of best practice; ongoing process review and improvements in every department; protection of those who report concerns through robust policies endorsed at Board level throughout an organization to eliminate the fear of retaliation; training in open, non-defensive team-working principles; and mediation structure and process for resolution of differences of opinion or interpretation of contradictory and volatile data.Based on analyses of other safety systems, workplace silence and interpersonal breakdowns are warning signs of defective systems underlying poor compliance and compromising safety. Remedying the situation requires attention to the root causes underlying such symptoms of dysfunction, especially the human factor, i.e. those factors that influence human performance. It is essential that leadership and management listen to employees’ concerns about systems and processes, assess them impartially and reward contributions that improve safety.Fundamentally, the safety, transparency, and trustworthiness of HPOs, both commercial and regulatory, can be judged by the extent of the freedom of their staff to ‘speak up’ when the time is right. This, in turn, consolidates the trust of external stakeholders in the safety of a system and its products.The promotion of ‘speaking up’ in an organization provides an important safeguard against the risk of poor compliance and the undermining of societal confidence in the safety of healthcare products.

Individual Case Safety Reports ― How to Determine the Onset Date of an Adverse Reaction: A Survey

AbstractBackground: The building blocks of a pharmacovigilance system depend primarily on good quality individual case safety reports (ICSRs), which are stand-alone summaries describing one or more suspected adverse reactions that occur while a subject is taking either an investigational or marketed medicinal product and may require expedited reporting to regulatory authorities. For regulatory reporting purposes, the information of an ICSR is usually captured on forms such as MedWatch 3500/3500A, CIOMS I, Vaccine Adverse Event Report System (VAERS) or Adverse Events Following Immunization (AEFI). ICSRs that are sent electronically must meet the standards for electronic transmission specified in the International Conference on Harmonisation (ICH) E2B (R2) guideline. In filling out these regulatory forms, there are some areas of ambiguity. One of these is what the ‘date of event’ (MedWatch) or ‘reaction onset date’ (CIOMS) is interpreted to be. Objective: The aim of the survey was to determine the uniformity of responses for the onset date of an adverse reaction. Methods: A pilot and three surveys of pharmacovigilance professionals were undertaken between February and July 2009 to determine the range of responses for the onset of an adverse reaction. A narrative of a subject admitted to hospital with a diagnosis of pneumonia was presented and the respondent was asked to pick the date of onset of the adverse reaction. Results: The total number of respondents was 129. The results of the surveys indicated there was considerable variation in responses. These differences were based on different perspectives regarding the suspected adverse reaction. Some viewed the ‘reaction’ to be the first onset of signs and symptoms (even if nonspecific), others considered the onset of the reaction to be the date of the diagnosis, while others considered the date to be when the reaction became serious. Conclusion: By means of a survey, we have illustrated an example of the variability of determining the onset date of a suspected adverse reaction, and recommend that a criterion for onset time, i.e. beginning of signs or symptoms of the event, or date of diagnosis, be chosen as the standard. Once decided, this information should be incorporated into the company’s case assessment documentation and staff appropriately trained, thus ensuring consistency across cases and minimizing the time spent in determining what date to use.

How to Apply the Human Factor to Periodic Safety Update Reports

Society has been increasingly intolerant of excuses for systems breakdown in many areas of public life. This is hardly surprising given that there is overwhelming evidence behind why processes fail and mistakes are made, and so, based on this evidence, processes should be designed to mitigate risk. The main root cause of many process failures can be attributed to the human factor, which encompasses all those factors that can influence people and heir behaviour. Based on experience from other safety-conscious industries, there is a major move to manage the human factor as part of delivery of safety culture in healthcare systems. Since pharmaceutical companies are healthcare companies, it makes sense that the principles underlying a pharmaceutical safety culture are aligned with those of the healthcare sector. A good place to start applying human factor management to a pharmaceutical safety process would be the complex process required to produce a good quality Periodic Safety Update Report (PSUR) on time and to an acceptable format. This can be achieved by a process aimed at building on an ongoing learning cycle through planning, observing if execution matches expectations and learning from mistakes and through the interdependent teamwork of PSUR contributors providing mutual support. Such a framework of teamwork and communication principles can be applied to the entire process for the preparation and submission of PSURs.

Managing the Interface with Marketing to Improve Delivery of Pharmacovigilance Within the Pharmaceutical Industry

The pharmaceutical industry is under pressure to improve the scientific quality of its decisions concerning the benefit and risks of its products while ensuring compliance with acceptable standards of marketing. All those in a pharmaceutical company who currently work within pharmacovigilance should be encouraged to lead from the front to examine ongoing marketing activities to see how they can be adapted more towards pharmacovigilance and risk management. The current irony is that the personnel who have the greatest influence on benefit-risk decisions of a product are not necessarily those who acknowledge that they are performing pharmacovigilance. Indeed, for all concerned, whether their orientation is scientific and commercial, effective communication with prescribers and consumers usually underpins product success. Also, a substantial ‘marketing’ budget is culturally acceptable for the pharmaceutical industry so it is logical to assume that resource for postmarketing activity is often made available. Given these realities, I suggest we should strive for an integrated marketing and risk-management plan based on the best available evidence and that being fully aware and in control of the safety issues for your products is the best way to commercialise them successfully. This approach can still be consistent with other corporate responsibilities such as trying to reduce the financial burden of product development. If this article stimulates further debate about how the pharmaceutical industry can more effectively organise resources and operations to support pharmacovigilance, risk management, and marketing, then it will have achieved its purpose.

An aviation perspective of safety in the pharmaceutical sector

In order to rebuild society’s confidence in the safety of medicines, we suggest the fragmentation, increasing complexity and inefficiency of the pharmaceutical safety system might be addressed by extrapolating from best practices of other safety conscious sectors. This is consistent with what the Institute of Medicine advised in their seminal report in 2000. Research from the MIT Department of Aeronautics and Astronautics has shown that modern socio-technical systems are becoming more complex and tightly coupled in response to demands for increasing performance and cost requirements. Thus understanding such systems and analysing how processes behave have become correspondingly harder. This is well illustrated by the example of how the EU pharmacovigilance guidelines have increased in complexity from the first version published in 1999 and the final version of Volume 9A released in March 2007. In both versions are the words ‘The marketing authorisation holder must ensure that it has an appropriate system of pharmacovigilance in place in order to assure responsibility and liability for its products on the market and to ensure that appropriate

An Update on ISoP Special Interest Groups (SIGs)

Special interest groups or ‘SIGs’ are becoming an increasingly important part of the International Society of Pharmacovigilance (ISoP). SIGs are groups of ISoP members working on a specific pharmacovigilance topic relevant to the scope and aims of ISoP, which are primarily education, training and promotion of research for the benefit of patients. Currently, there are SIGs on women’s medicines, risk communication, and risk minimisation for Asian countries. A new SIG on herbal and traditional medicines was created in April 2017 and will be launched formally at the ISoP 2017 annual conference in Liverpool, UK. In this article, we describe the ongoing work of ISoP with the existing SIGs and introduce the two new SIGs under development. SIGs operate as global networks without regional limitations. While they exist primarily to connect ISoP members, they may also engage non-ISoP members with special expertise in the topic concerned. In addition, a SIG may work together on its specific topic with other groups, associations or societies outside ISoP, after agreement by the ISoP Executive Committee (EC). The instigator or instigators of a SIG usually take the lead to get the group off the ground and invite interested parties to become founding members and begin preliminary work. A coordinator or lead person is then chosen who cooperates closely with the ISoP Education and Training Program team and the ISoP secretariat. The coordinators of the current and developing SIGs are summarised in Table 1. As with all other ISoP activities, work within and for each SIG is voluntary. ISoP is a not-for-profit organisation with no paid positions other than the ISoP executive secretary, and ISoP members, including EC and board members, donate their time to this work. This year, the ISoP EC has strengthened its support of the SIG community by creating an over-arching SIG coordinator role and appointing a member of the advisory board to this position. This role is described in Sect. 4.