International Pharmacovigilance Day

The Clinical Trial Regulation EU CTR 536/2014 entered into force on 31 January 2022. This regulation is the basement of a broader initiative launched by the EMA to create a favorable environment for innovation and research in the EU. As per the ACT EU paper published by the EMA in January this year, an analysis of centralized marketing authorization applications has shown a fall in the inclusion of clinical trial results generated in the EU. The variety of requirements between EU Member States complicated the submission of clinical trials to take place in several EU countries. A changing environment during a rapidly evolving public health crisis the resulting slow approval process and associated high costs to perform clinical trials might in part explain this drop of multi-EU countries clinical trials.

The clinical trial regulation EU 536/2014 is regulating clinical trials in the EU. The ultimate goal of this regulation is to ensure a greater level of harmonization of the processes for assessment and supervision of clinical trials throughout the EU and it aims to ensure the EU offers an attractive and favorable environment for carrying out large clinical trials. It introduces an authorization procedure based on a single submission via the Clinical Trial Information system (CTIS) portal to all member states concerned at the same time, and an assessment procedure leading to a single decision on core documentation, coming along with rules on the protection of subjects and transparency requirements.

CTIS is the backbone of the new submission process in the EU as it supports the flow of information between clinical trials sponsors and regulatory authorities in the EU Member States and EEA countries, throughout the lifecycle of a clinical trial. EMA worked for over 7 years to develop this portal and sponsors are using it since a few months now. How are the first experiences with this portal?

EU member states’ readiness to apply this new regulation is another key aspect of the harmonization process foreseen by this regulation. The clinical trial regulation aims to harmonize the rules for assessing clinical trial applications and should ensure that these rules for conducting clinical trials are identical throughout the EU. Now that the first experiences on assessment have been collected, what does reality look like? Are member states ready to assess clinical trial authorization dossiers in a very short time, and are they sharing work and collaborating to issue a common assessment?

The presentation will summarize why this new regulation is having such a high impact on clinical trials sponsors and will describes challenges and opportunities this new legal framework brings with it.

The rapid globalization of good Pharmacovigilance Practices (GVP) has resulted in regulatory authorities expanding the level of their pharmacovigilance (PV) requirements to align with the existing European Union Good Pharmacovigilance Practices (EU GVP). These requirements include the Pharmacovigilance System Master File (PSMF) tailored to meet individual country/regional specific requirements.

Since the introduction of the EU GVP Module II guidance in 2012, which provided a framework that allowed varying organizational structures of marketing authorization holders (MAHs), the concept of the PSMF has evolved in countries/regions outside of the EU over the years, creating challenges related to maintenance and production of a PSMF (local or regional). It is therefore imperative that processes are put in place to overcome these challenges because through the production and maintenance of the PSMF, be it local or regional, the MAH and the non-EU local/regional QPPV should be able to verify if the PV system has been implemented in accordance with specified regulatory requirements and compliance.

As more and more health authorities/regulators both in and outside the EU increasingly expect the QPPVs to have oversight of all activities impacting PV, not just core PV activities, It is important to note that a compliant PV system requires effective interfaces with various stakeholders. E.g., regulatory affairs, quality assurance, product quality, medical information, etc. Hence, the QPPV must implement best practices to ensure adequate oversight of the PV system under their responsibility.

For regions outside the EU, e.g.  Latin America (LATAM) and the Arab region, the alignment of the local/regional PSMF with company`s EU or global PSMF is essential to ensure consistent information is delivered to regulatory agencies/inspectors globally. Also, this alignment will enable the non-EU local/regional QPPVs have adequate oversight of their local/regional PV systems and awareness of any updates on the global PV system that impacts the non-EU PV systems.

In the early 1990’s, mostly GCP and GMP inspections included aspects of Pharmacovigilance such as SAE management and associated activities. Although Pharmaceutical Companies were constantly preparing for PV Inspections, Health Authorities conducted limited Pharmacovigilance inspections which were mostly for new approvals or for-cause. With the coming of Volume 9A, systematic inspection programs were triggered by some Health Authorities (HA) such as ANSM (France), MHRA (UK), AIFA (Italy). MHRA then put in place a risk assessment questionnaire that pharmaceutical companies were expected to complete, those who did not complete were automatically on a higher inspection risk. Based on the analysis, MHRA conducted routine inspections mostly every three years, of course triggered inspections were also conducted. Other Health Authorities still conducted limited Inspections due to limited internal resources and training. The FDA did conduct CDER inspections under its BIMO Compliance programs. In Australia, Middle-East, LATAM, and Eurasia PV inspections were still not being conducted.
With the coming of the GVP in 2012, and the roll-out of Module III the Inspection conduct in the EU intensified. Obligations were laid out not just to MAH’s but also to the national Health Authorities expecting them to have detailed inspection programs, the types of inspections were better defined into routine/ for cause, pre-post authorisations, announced/ unannounced, re-inspections etc. EMA, PRAC, CHMP, European Commission also took a central role in Inspections working together with the national HA’s. The Rest of world followed, with implementing the GVP in Arab Countries, Eurasia, and countries like Japan (PMDA) and Australia (TGA), Health Canada also setup their Inspection programs. Several national European Health authorities started to systematically roll out questionnaires to pharmaceutical companies to help them make a risk assessment for their Inspection program such as ANSM, BfArM (Germany), IGJ (Netherlands), OGYEI (Hungary) etc. PV Inspections in the USA were defined as Post marketing drug experience (PADE) focusing on standard PV topics of case collection or Risk Evaluation and Mitigation Strategies (REMS) Inspections focusing on risk minimization or mitigation activities laid out during drug approval.
Over time, the kind of inspections being conducted has changed. E.g. MHRA now has a revised inspection model with four types of Inspections: Routine PV, Routine risk management and safety communication, additional risk minimization measures (aRMMs) and Non-Interventional PASS. The COVID 19 pandemic also influenced remote Inspection conduct. Currently Inspections are done either remotely, on-site or a mix of both. Inspection findings are now shared by HA’s with each other and metrics and trends are shared with the public.
In the past, limited Pharmacovigilance audits were conducted by pharmaceutical companies, mostly of the vendors who undertook key tasks in case management etc. Although, Vol 9A had some requirements clearly stated for conduct of PV Audits, the requirements for a risk-based audit program with an audit strategy and tactical and operational planning for audits kickstarted with coming of GVP Module I and IV. Pharmaceutical companies in Europe then setup a PV audit universe defining clear entities for audits (vendors, systems, partners, affiliates, IT systems, special programs) and conducted an ongoing and annual analysis based on risk criteria for the various entities.
Over time however additional entities have been included into the audit universe such as for a PASS program the tool and systems, vendor, site, documents also need to be audited. Market research vendors, or vendors managing patient assistant programs now form a part of the audit universe and must be audited.
Companies have been required to setup separate units within Quality assurance for PV audits and a resource pool of trained PV auditors needs to be developed.
The type of findings identified has also matured over the years. Although typical case processing related findings (collection, reporting, follow-up, pregnancy) are still identified, observations related to reference safety information management, risk effectiveness checks and minimization measures are seen more and more. Quality management system associated gaps continue to be seen in procedures, audits and CAPA management. The differences in legislation between countries has also been a challenge for pharmaceutical companies to implement a harmonized process across the organization, so one size does not fit all.

The pharmaceutical Industry applies a QMS based on the ICH Q10 Pharmaceutical Quality System. It describes one comprehensive model for an effective pharmaceutical quality system that is based mainly on International Standards Organization (ISO) quality concepts described on the ISO 9001 certification, which is widely used across the product lifecycle and in customer-oriented service organizations. The ISO 9001 delivers a system of continual improvements driven by customer’s needs, and although its purpose is driven by business needs, the ISO 9001 principles has spread widely into the back-offices of the pharmaceutical industry, including departments involved with clinical studies and post-marketing safety surveillance.

The concept of key performance indicators (KPIs) is described in chapter 9 in ISO 9001:2015. KPIs are used to describe the performance of the QMS. Examples of data to monitor and measure include customer satisfaction, nonconformities, effectiveness of risk management and external provider performance. A frequent follow up of KPIs allows for an early detection of possible gaps as well as improvement opportunities.

Similar principles are described in the Good Pharmacovigilance Practises (GVP) module I (I.B.12) that came in effect in 2012. Managerial staff is required to monitor the performance of the QMS system at regular intervals in a risk-based manner. Audits obviously comprise an important component in this monitoring, however, establishment of KPIs that continuously monitor the requirements across the GVP modules and across the daily quality activities that manage the QMS appear highly recommendable for both managerial staff and QPPV overview of daily-weekly-monthly-annual compliance monitoring.

Demonstration of managerial and QPPV overview of the PV system is key and consequently always part of regulatory inspections of pharmacovigilance organizations. How this play out in practice in the pharmaceutical industry is largely dependent on the organization supporting the commercialization its products or provision of supporting services.

Good Pharmacovigilance Practices (GVP) module I (I.B.12) sets out the principles of key performance indicators (KPIs) in relation to the quality requirements for pharmacovigilance. KPIs for some key activities described in the GVP modules seems relatively straight-forward to establish, e.g. compliance to ICSR submission timelines, compliance management with contractual partners or submission compliance for PSUR, RMPS or addendums to clinical overview (ACOs).

However, establishment of meaningful KPIs represent a challenge for some other interfacing PV areas, e.g. compliant management of product complaints, medical information, vendor management, and not least within the monitoring of interventional/non-interventional studies, patient support programs, market research, additional risk minimization activities, and product label updates.

Like instruments in a cockpit, KPIs are both required and needed to maintain a managerial overview. Their practical application and subsequent management when non-compliance is detected is where you may find your helicopter instruments recording some turbulence.

Pharmacovigilance is a particularly global discipline. Pharmacovigilance and Risk Management strategies are developed at a worldwide level to ensure all patients, regardless of their location, can count on the same level of safety monitoring and on the same proactive risk minimisation measures to minimize the risks associated with the use of medicines, including communication on risks to HCPs and patients.
At the same time, the implementation of pharmacovigilance and risk management activities is subject to local and regional regulatory requirements and potentially to local clinical practice.
The local affiliate pharmacovigilance team is where global strategies meet local requirements. Depending on the company, the roles and responsibilities within the scope of local affiliate pharmacovigilance are clearly defined, with the aim to achieve global standardisation of activities across the markets. The local pharmacovigilance department is routinely informed of any issues impacting patient safety by headquarters and vice versa. The local team acts as the local subject matter expert for topics such as safety related queries from internal and external stakeholders, including advising on the local regulatory requirements, audit and inspection readiness, adverse event reporting, pharmacovigilance wording in contracts or social media monitoring.
The range of responsibilities that converge in the affiliate pharmacovigilance department will be discussed in more detail, as well as the interactions with various partners, including the company headquarters.

Risk minimization measures (RMMs) are interventions intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient should they occur. Risk management plan defines suitable RMM(s) for each of safety concern related to medicinal product. For majority of medical products, safety concerns are managed with routine RMMs, however, for certain products additional RMMs need to be implemented. Both marketing authorization holders and national competent authorities (NCAs) have legal responsibility to monitor outcomes of RMMs (Directive 2001/83/EC, Regulation 726/2004) since key to effective risk management is not only to implement, but also to verify whether indeed proposed measures work. Generally, effectiveness evaluation applies to additional RMMs, however, it is not always easy or possible to perform the evaluation. In the presentation challenges about planning, implementing and measuring of effectiveness of RMMs from NCA’s point of view will be discussed together with possible strategies to mitigate them.

Medication is the most frequently applied medical intervention in medicine, and helped us to prolong life expectancy and improve quality of live. However, medication is also one of the least supervised medical interventions as most medications are taken beyond the front door of the patient in absence of the caregiver.
As most risk minimization programs aim to reinforce medication use behaviors and actions that support the safe use of that medication, risk medication programs should be designed to support patient in their medication intake and medication evaluation at home. This requires the right content of the patient education, with a priority which information should be communicated first, in a best possible communication channel and in the right context.
Combining his experience as practicing (outpatient) pharmacist/clinical pharmacologist with his scientific background as professor in personalized pharmaceutical care, professor Bart van den Bemt will reflect on current risk management strategies and the suboptimal implementation of these strategies in Dutch clinical practice. As risk minimization programs are an important tool for safe medication use, Bart will explore how existing strategies can be further improved to optimize the effect of risk minimization in the homes of the patients.

Have you ever thought that the International Pharmacovigilance Day could also be International (Pharmaco)vigilance or even International Vigilance Day?
The purpose of this presentation is not to change the scope of the conference, but to further broaden the horizon of vigilance to other product safety categories.
Pharmacovigilance is responsible for monitoring the safety of medicinal products for human use. But is it the safety of medicines only that should be monitored and assessed? Can’t humans or other animal species gain benefit or be harmed by non-medicinal products?
Hence, the primary concern is again about safety. Medical devices, diagnostics and Healthcare IT (Materiovigilance), cosmetics (Cosmetovigilance), food supplements and nutritional products (Nutrivigilance), and animals’ drug safety (Veterinary pharmacovigilance) are nowadays well-regulated although they are subject to a different regime than medicinal products. The basic principle of these types of vigilance is still ensuring a safe use of product, updating information and taking all measures required so that this never fails. However, there are several differences between the surveillance expected for medicinal products intended for human use versus a veterinary drug as well as between medicinal products and non-medicinal ones. Even vaccines and biologics, a diverse group of medicines, are governed by specific requirements.
The presentation will summarize the basic requirements that a company needs to meet for all its products on the market to ensure safety and compliance, and reduce risks.

During this interactive session, participants will be divided in groups and will have the possibility to discuss about one specific topic, guided by an expert chair. After 20 minutes, groups will change and face a different subject.

Key topics are:

1. Social media monitoring
2. PV system integrations due to mergers and acquisitions
3. Loss of exclusivity (generics + innovator risk minimization)
4. PV Technologies and automation

At the end of the discussion, everybody will come back to the plenary session and each moderator will sum up the main points suggested by the groups.

This year we are looking back to 10 years of experience with the so-called pharmacovigilance legislation that came into force 2012. The world of pharmacovigilance has substantially changed since that time, and will further evolve in the future. It is time to take stock and to reflect upon how pharmacovigilance would or should look like in 10 years from now. Promising developments are ongoing as regards the availability of big data with advanced analytical approaches or new technologies including artificial intelligence. They will become important tools in pharmacovigilance in the near future but the question remains whether they are to be considered real game changers.
New opportunities in terms of technical advancements will require the adaptation of the regulatory framework including the legislation, not only in Europe but also from a global perspective. Collaboration will be key – between regulators, industry and other stakeholders including academia, but also between the European regulatory network and the rest of the world. Last but not least the pandemic has shown both the strength of the current system and the challenges we are all facing. It is therefore essential to benefit from the lessons learnt to be prepared for any future scenario.

In this last part of the conference, the Scientific Board invites you to participate in a highly interactive session on various pharmacovigilance topics. With everyone’s support, including speakers’ involvement, they will guide you through a variety of interesting facts. To test your knowledge, trigger some last discussions, interact with each other, or simply as food for thought. Also, they will close out the International PhV Day by reflecting on some of the key messages learned. All in a fun and constructive way, LS Academy aims to leave you inspired, energized, and socialized!