Practical considerations for creating a strategic and proactive clinical safety and pharmacovigilance organization for the future

1.1.Context of PS in the pharmaceutical industry

As comparatively newer functional groups, PS departments initially settled at the periphery of influence within pharmaceutical companies with some variability in the remit regarding pre-clinical safety, clinical development safety, and/or post-marketing safety, especially in those companies where the PS department’s remit was clinical development and post-marketing safety. We consider this was largely due to the early focus on operational matters such as a compliance-driven processing of ICSRs and associated aggregate reports. Within the industry, such activities are referred to as license-to-operate activities, as they adhere to regulatory requirements. PS departments are generally proficient at performing such routine PV tasks.

However, strictly meeting license-to-operate requirements did not meet the increased expectations of a modern PS department, which include prioritisation of safety concerns in order to de-risk pharmaceutical product development along with characterisation of the combined benefit–risk profile and associated risk minimisation activities.

At the same time, PV and drug development are becoming increasingly heavily regulated by health authorities, with new countries, for example China and nations in the Middle East, setting up comprehensive PV regulatory frameworks. These are mainly based on well-established models like the EU Good Vigilance Practice (GVP), for instance in Brazil and Mexico, or the United States Food and Drug Administration (FDA) Regulation, but the requirements could be adapted or amended which call for separate, often complex, solutions. Some National Authorities, for example Health Canada, have significantly increased their activity level in the PV area, which means increased demands on pharmaceutical companies to supply advanced compilations and analyses.

Even if some countries are adopting frameworks building on the EU GVP, there is also the notice of a growing divergence between existing regulatory authority legislative frameworks, illustrated by the contrast between the FDA and the European Medicines Agency (EMA) on the principles for causality assessment of potential Suspected Unexpected Serious Adverse Reaction (SUSARs) in a clinical trial setting. This nonconformity obviously causes a need for parallel processes.

To stay competitive, a modern PS department needs to be ready to embrace advancements in scientific, technical, and digital capabilities. For investigational products, examples include increasing expertise in translational aspects of preclinical testing (such as the drug-induced liver injury modeling tool, DILIsym^®, to predict liver injury), the use of exploratory biomarkers (such as glutamate dehydrogenase and sorbitol dehydrogenase to detect liver injury), proactive PK/PD (pharmacokinetic/pharmacodynamic) modelling for certain safety topics, as well as internally generated novel working tools to better quantify the concepts of signal strength and medical importance. For marketed products, examples include predictive drug safety exploiting modelling of available datasets, the power of big data for signal evaluation, and robotic process automation for case processing.

Lastly, it is widely recognised that patients, physicians, national healthcare providers, and insurance companies demand the use of safer pharmaceutical products. In fact, the safety of these products is a competitive, differentiating factor in their utilisation [6–8].

1.2.Internal setting

AstraZeneca, a large-cap pharmaceutical company with a long history of delivering small drug molecules to market, has subsequently acquired several small and mid-sized biotechnology companies, e.g. MedImmune, which have largely operated as quasi-independent subsidiaries. For instance, the PS groups at AstraZeneca and its biologics subsidiary MedImmune operated cooperatively in parallel (e.g. sharing critical systems), with each focusing on their respective organisation’s product remit. The organisational structures in AstraZeneca and MedImmune PS respectively were, however, quite different.

By 2012, these parallel PS groups were facing multiple challenges, from a scientific and structural perspective:

In 2013, the groundwork for a strategic reorganisation and uplift of the PS function was formulated under the name of the “One Patient Safety” (OnePS) initiative. With the overall context of merging the AstraZeneca and MedImmune Patient Safety organisations, the initiative consisted of two pillars:

There were three purposes of the OnePS initiative: (i) to facilitate the combined operational safety administration of the legacy AstraZeneca and MedImmune PS organisations; (ii) to move from a reactive safety management-focused organisation to a proactive, strategy-focused organisation; and (iii) to adapt the organisation to the changing context of the AstraZeneca R&D business described above.

The objective of this article is to describe how AstraZeneca has reorganised and focused its PS function towards becoming a strategic and scientifically competent driver of drug product safety for patients.

2.1.OnePS operating model

To achieve the objectives described above, the initial step was to develop upon existing ways of working and procedural guidances that would add true value to projects. The OnePS project was delivered with internal resources (except for limited vendor support with interviews and communications). This included internal change and project management expertise and leveraged the considerable subject matter expertise within the PS departments. Five focus groups were established concentrating on specific procedural areas as described below. Group members were selected to provide a diversity of representation with regards to geographic region, as well as level of experience and organisational background. In all groups, cross-functional participation was sought to ensure input from key interacting functions (e.g. clinical, biostatistics, regulatory, and toxicology) and other internal stakeholders (e.g. local affiliates/marketing companies and project leadership).

The five focus groups explored the following topics:

For some of these focus areas, pre-existing analyses and initiatives were already identified as part of previous improvements. Examples of pre-existing analyses include a root cause analysis of safety failures in early clinical studies carried out as part of the analysis of early development performance in AstraZeneca as already described [9]. The focus group that was concentrating on competency build in PS incorporated previously established competency and training grids into their work.

Of the main outputs from these five focus areas, three were applied to the new operating model, specifically: a value-stream map defining eight discrete steps with a description of key activities per step; a renewed PS product/project team structure to support this; and a definition of roles and responsibilities for teams and key members (resulting from a Responsible, Accountable, Consulted, and Informed [RACI] analysis [11]). These are further described below.

2.2.Eight value-adding steps

To establish an output structure, Lean Six Sigma methodology [12] was applied. An overall value-stream mapping analysis was performed with the aim to embrace all aspects of clinical safety input into drug projects and products. From this analysis, eight discrete value-adding steps were defined (see Fig. 1) covering all phases, from preclinical to post-marketing activities for mature brands.

Fig. 1.

PS high-level value stream map covering drug development, life-cycle management, and maintenance: Eight discrete value-adding steps. Duplicate activities indicated by ‘a’ in the clinical development space and ‘b’ for post-marketing, in which data sources differ. To describe key activities per step, the steps were split. However, the majority of marketed products have ongoing clinical development/life-cycle management activities, so ‘a’ and ‘b’ activities will be ongoing in parallel. BRAT: benefit-risk action team; CDS: core data sheet; CTD: common technical document; DSUR: development safety update report; Dvt: development; EHR: electronic health record; HCP: healthcare professional; IB: investigator’s brochure; ICSR: individual case safety report; ISS: industrial safety services; PBRER: periodic benefit-risk evaluation reports; PS: patient safety; PSUR: periodic safety update reports; Reg: regulatory; RMP: risk management plan.

For each of these value-adding steps, for all representing areas where contributions from PS are impactful for drug projects and products, the teams worked up a succinct description of the key activities per step to drive value and visibility of Patient Safety’s contributions. An example of such an output is provided in Textbox 1; a full graphical representation of these activities is available as Supplementary Fig. S1 in the supplementary material.

2.3.Safety product/project team structure

To deliver the identified value-adding activities, the PS drug project team structure was reassessed. A revised team structure was proposed taking into consideration lessons learned from prior implementation. As the PS team would need to work across all phases of drug development, from preclinical to post-marketing for mature brands, a lean and flexible team structure was needed. To fulfil this, an operating model was established by which the clinical safety/PV work would be delivered via two teams. This means that tasks commonly described as safety science and risk management for a project/product are the focus for the two teams. It is worth noting that routine safety work, such as case handling, basic literature monitoring, and signal detection, as well as periodic safety report management, is performed in partnership with a third-party vendor. The activities performed by the vendor were not impacted by the change in the revised team structure.

The two team structures, the Safety Strategy and Management Team (SSaMT) and Safety Surveillance Team (SST), and their respective membership are presented in Fig. 2.

Fig. 2.

Clinical drug safety/PV project/product work delivered via two teams: Lean team structure with agenda-driven memberships, same for all phases/science units. Experts indicate agenda-driven membership from across functions as needed, e.g. epidemiology/real-world evidence, biostatistics, clinical pharmacology, clinical operations, and quality assurance. GCL: global clinical lead; GRL: global regulatory lead (key member for late-phasing project); GSP: global safety physician; PS: Patient Safety; PVS: pharmacovigilance scientist; Study Phys: clinical study physician/medical monitor; SSaMT: safety strategy and management team; TPL: toxicology project lead (key member for early phasing projects).

The SSaMT:

In summary, the SSaMT is the main body for individual product safety decision making, for EU marketed products, together with the European Union Qualified Person for Pharmacovigilance (EU QPPV, see below).

The SST is a PS-led team consisting of the Global Safety Physician, the SSaMT Leader and, depending on the size of the programme, additional safety/clinical physicians and scientists, with the core remit of reviewing safety data from all sources at project level. Depending on phase of development and complexity, one SSaMT and Surveillance Team can handle one or many compounds, the latter common in early development (Phase I–IIa) and for mature, established brands.

2.4.PS Centre of Excellence

In addition to these two drug-project safety teams, the PS Centre of Excellence (CoE) was an integral part of the reorganisation. The CoE is a cutting-edge scientific consultative hub proactively working to advance the science of clinical drug safety and PV. In particular, the CoE hub is supporting:

In the new merged organisation, the office of the EU QPPV, responsible for the PV system including all EU marketed products, is also located within the PS CoE.

2.5.Safety operations, process, and compliance

Support for safety operations, process, and compliance was provided by two organisational sections. These two sections collectively supported:

2.6.Roles and responsibilities for teams and key roles

As the final step to creating the operating model and to provide a basis for authoring the new procedural documents for the integrated PV system, a RACI analysis was performed. The RACI covered all the activities identified under the eight value-adding steps in the value-stream mapping. In the RACI analysis, Responsibility (R), Accountability (A), Consulted (C), and Informed (I) were assigned both at team level (e.g. SSaMT, surveillance, global project, and clinical project teams), and also for key roles inside and outside the PS departments (e.g. Global Safety Physician, SSaMT Leader, EU QPPV, Global Clinical Lead, and Global Regulatory Lead). The full analysis resulted in a 258-row (activities) by 36-column (teams and roles) table. Fig. 3 demonstrates how the operating model and RACI relate to the build of the OnePS procedural framework and integrated PV system.

Fig. 3.

Building blocks for an integrated PV system. Following the definition of the project approach, a pre-work phase was performed to (i) create an inventory of all current AstraZeneca and MedImmune PS department-owned procedural documents; (ii) collate all key global PV regulations, directives, and guidance (clinical trial and post-marketing); (iii) create the OnePS workstream book; and (iv) create the OnePS procedural document templates. PS: patient safety; PV: pharmacovigilance; QA: quality assurance; RACI: Responsible, Accountable, Consulted, and Informed.

2.7.OnePS procedural framework

Following the creation of the OnePS operating model, an updated set of procedural documents was needed. A procedural framework is critical in pharmacovigilance as it sets the foundation for transparent and traceable ways of working and processes, of importance not only to demonstrate compliance with legal and/or regulatory requirements, but also to ensure quality and consistency of activities and communicate best practice across an organisation. Certain elements were considered fundamental to its delivery, for example, it was recognised that the existing documents may not represent the most efficient and simplified documentation of the PV system and new ways of working. Standard operating procedures had been amended over time as a result of business or regulatory changes/inspections and had become lengthy to review and maintain. In view of this, OnePS represented a unique opportunity to start afresh and develop a new suite of PV procedures.

Existing global PV regulations and guidelines, including European GVP modules, FDA regulations, and CIOMS guidances, together with analyses of AstraZeneca/MedImmune regulatory authority inspection findings, were the foundational building blocks for the new procedures. Other building blocks were the new PS operating model, along with the associated and detailed RACI document. These building blocks informed the key principles and guided the framework for the ultimate delivery of the new standards, procedures, and guidelines, as illustrated in Fig. 3.

2.8.Planning tool – workstream book

A list of all activities and deliverables required from the PS department to meet the global regulatory requirements was created, detailing each specific requirement with the following information mapped out:

Input was sought from additional cross-functional representatives to aid in completion of the full details described above.

2.9.Document production

Each workstream was responsible for planning the delivery of new procedural documents required to cover the scope that was allocated via the workstream planner. Drafts of new procedural documents were prepared after identifying the workstream deliverables. Document deliverables were identified and tracked across all workstreams. Draft documents authored using the OnePS procedural document templates were reviewed internally by the workstream before being released for official document review.

An approach was agreed for the standardised review of project deliverables by PS representatives outside of the production workstream and by appropriate functions/groups outside of PS. For each new procedural document, the affected functional groups (PS and non-PS) who needed to review the documents were documented and were centrally recorded on the overall delivery plan.

2.10.Consistency check

Once the reviews were completed and final versions of the documents had been created, these were submitted for a final consistency check. A consistency check process was established and performed by the AstraZeneca EU QPPV, deputy EU QPPV and a member of the OnePS implementation team to review all new procedural documents produced by the workstreams to ensure:

Once complete, the documents were submitted for approval and publishing via the AstraZeneca quality management system. Upon approval of the new procedural documents, legacy documents were retired from internal systems. Standard “read and sign” training was assigned to staff via the company’s learning management system.

2.11.Training

Following the delivery of the new procedural documents, a curriculum of live training sessions was created to supplement the standard “read and sign” training approach that had been used internally. This live training focused on key changes from the legacy procedural documents and provided an overview of the process(es), implementation plans, and toolkit items. Each training session covered one or more procedural documents from a given workstream with one or more sessions per workstream.

As part of the creation of the new procedural framework, a decision was made to procedurally formalise the administration of clinical safety across all science units by creating an internal Standard. Within the AstraZeneca clinical quality framework, the internal Standard represents a high level, widely applicable and mandatory document. A key element was to newly define the SSaMT (i.e., safety strategy and management team), and to create a new AstraZeneca executive safety board (chaired by the Chief Medical Officer, together with the Head of Global Regulatory Affairs, PS, and Quality Assurance [GRAPSQA] as the co-chair).

The standard also brought new clarity to the definitions of safety strategy and the overarching purpose of the PS function within our organisation: “… safety strategy implies the anticipation and prioritisation of potential safety concerns, understanding their possible consequences, and the proactive development of appropriate management plans to address those concerns and consequences”. Similarly, the standard clarified the goals of PS: “PS primary functional goals (are): robust and fit-for-purpose, license-to-operate activities, preferred-partner, gold-standard level of strategic PS expertise, and the careful identification, characterisation, communication, and management of safety risks”.

Given the growing recognition of the need to focus PV oversight into developmental programmes, a new foundational document, the SSaMT Plan, managed by the safety function, was introduced. It was recognised that the older developmental risk management plans, which were generally based on the EU risk management plan template that focused on approved products, did not always adequately address the unique challenges associated with the development of investigational products. While the SSaMT plan contains a risk log, it has additional modules to ensure consistency of safety messaging within projects, memorialisation of safety-related decisions and signal tracking, and provides a comprehensive checklist of strategic safety considerations for various development milestones along with instructions on extrapolating these considerations into potential consequences, such as labelling or health authority pushback.

Another new, key element in this procedural transformation was an increased focus for PS input and oversight newly focused at the time of certain developmental milestones: first-in-human clinical trials, as well as investment decisions for phases II and III, and commercialisation. Review by a newly created internal PS peer review board is required at these milestones to review key safety risks within the SSaMT Plan to better inform key milestone decisions.

3.1.Procedural document simplification

Procedural documents remain a fundamental part of the PV quality system. PS departments dedicate significant effort to ensure all employees receive appropriate training on procedural documents and in maintaining these documents based on changes in regulation and in alignment with other internal documents. Quantitative measures of the simplification effort were felt to be important in measuring not only the impact to staff but all ancillary activities stemming from procedural documents. Parameters to assess workload on staff and effort to maintain documents included: overall number of documents, number of pages, and total word counts. Data were collected for the legacy documents (AstraZeneca and MedImmune) and for the new OnePS procedural documents.

Table 1 presents the number of procedural documents covering various topics from the old PS departments, the associated pages and word counts from those documents before the OnePS initiative, and the positive results of simplification gained from combining the two legacy document systems into one updated system (‘New OnePS Docs’). In short, there was a 71% decrease in the total number of procedural documents using the OnePS approach, as well as a 64% decrease in the number of pages and a 56% decrease in total word count, all exceeding the 50% reduction expected from halving the numbers of two joined frameworks. These measures of simplification were estimated to also result in a saving of five FTEs annually for document maintenance activities.

3.2.Internal customer feedback

As the project set out to implement new ways of working through the establishment of a new operating model, the PS department staff were integral in providing feedback on the project. Research was facilitated by a third-party vendor for this purpose, measuring employee engagement and message retention of global PS staff. The same vendor was used for assessment of all activities and the feedback was used to shape further communication to all staff following the roll-out of the OnePS process.

Face-to-face focus groups and phone interviews of several dozen therapeutic area (TA)-aligned safety staff were arranged across the major geographic footprint sites (US, UK, and Sweden) supporting global R&D activities before the full OnePS roll-out to establish a baseline and, subsequently, after the roll-out to assess interval progress. The question sets predominantly used open-ended questions focusing on OnePS communications and understanding; as such, results were primarily qualitative.

Baseline evaluation found that global PS staff characterised the department as having dedicated staff with good technical and collaboration skills; this remained true with interval follow-up. The most relevant interval changes noted after roll-out of the PS operating model were an increase in the feeling of empowerment and efficiency of safety staff. However, feelings of being overwhelmed and confused by the many changes were also expressed. The feedback suggested that continued effort on change management would be needed to enable adaptation of staff to new ways of working. Word clouds highlight the most frequently recorded individual qualitative concepts summarising this internal change is shown in Fig. 4 (A representing positive associations and B negative associations).

Fig. 4.

OnePS qualitative feedback word maps post-implementation. (a) Positive associations. (b) Negative associations. OnePS: One Patient Safety.

In addition to this survey of global safety staff, a more quantitative survey focusing on the usefulness of the updated OnePS procedural documents was sent to a larger audience (n = 148) of both global PS staff (TA and delivery/enablement) and local PS staff located in various local affiliate/marketing company settings. As with the pulse check, a third-party vendor was used. Questions were rated on a scale of 1–10 with aggregate average responses tracked. A consistent 10–20% increase in average scores was noted with an average of 0.96 indicating a real improvement in the usefulness of the updated procedures. This was viewed as a meaningful change indicator for the procedural documents when considering the initial feedback on the OnePS operating model and timing of this assessment which was performed 6 weeks after the release of the new procedural documents. Table 2 shows the questions used, as well as the results.