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Challenges and Future of Pharmacovigilance (PV) Compliance

The rapid and effective identification and assessment of safety issues with medicinal products are dependent on early access to complete information. This is fundamental to Health Authorities (HA) and Marketing Authorization Holder’s (MAH) abilities to protect public health by taking appropriate action swiftly.

In this regard, the HAs have an obligation to ensure guidance and regulations are enacted to govern Market Authorization Holders and ensure they understand implications of noncompliance with pharmacovigilance (PV) regulatory obligations that could result in potentially serious public health concerns and legal ramifications.

For many years, the Health Authorities have been working to facilitate MAH in meeting PV regulatory obligations. This includes the development of guidelines, organizing awareness programs, responding to enquiries, and electronic reporting. The HAs constantly monitor MAHs for non-compliance and take appropriate regulatory action when necessary.

Below is an outline of how compliance monitoring should be performed as per European Medicines Agency: All MAHs must have an appropriate PV system in place. This system should be capable of taking appropriate actions as mentioned below:

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Expedited Adverse Event (AE) reporting within fifteen calendar days of receipt by the MAH

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Periodic Safety Report (PSR) reporting

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Responding to requests for information from HAs

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Handling of urgent safety restrictions and safety variations

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Meeting CHMP commitments (where MAHs hold a centralized marketing authorization)

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Continuous monitoring of the safety profile of the authorized medicinal products and notifying HAs and health professionals regarding the changes to the benefit/risk profile of products

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Having a robust signal management process and taking appropriate measures to minimize risk

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Internal Quality Control and Quality Assurance and audit of the PV system.

Expedited AE Reporting

The purpose of expedited AE reporting is to make regulators, investigators, and other appropriate stakeholders to be aware of the latest and important updated information about the serious adverse drug reactions (ADRs). Therefore, such reporting will generally involve events that were previously unobserved or undocumented, and a guideline is required in order to define an event as “unexpected” or “expected” (expected/unexpected from the perspective of previously observed, and not on the basis of what might be anticipated from the pharmacological properties of a medicinal product).⁷

The methods employed by the HAs to prospectively monitor compliance with expedited AE reporting may include the following aspects¹:

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Determine any failures to report AEs by monitoring the AE reports received by all listed MAHs

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Monitoring the time between the receipt of AE reports by the MAH and submission to HAs to detect late reporting

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Checking PSRs to ensure all qualifying serious reports have been expedited

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Sample quality review of ICSRs to ensure quality and compliance, and launch inspection if found to be non-compliant

Periodic Safety Reports

The PSRs are an important PV document that provides an opportunity for MAHs to review the safety profile of their products and ensure that the Summary of Product Characteristics and Patient Information Leaflet are up to date. They also provide HAs with a valuable source of consolidated safety data. Due to these reasons, HAs emphasize on compliance with periodic reporting including submission timeliness, report format, comprehensiveness, completeness, and quality report.¹ In addition, the MAH has to ensure that the comments received from the HA assessor of periodic reports have been adequately addressed in the response document and in the subsequent report. There has to be a mechanism implemented by the MAH to track HA assessment reports and quality reviews to ensure the assessor’s comments have been addressed in the subsequent version.

The PSR/MAH would be considered noncompliant for the following reasons:

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Non-conformance to submission timelines: complete non-submission of PSRs, submission outside the correct cycle or outside the correct time frames (without previous submission of a type II variation), and non-restart of the cycle of submission when necessary

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Format of the document/report not in accordance with notice to MAHs

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Concealment of information particularly in the following sections of the report: Update Of Regulatory Authority Or MAH Actions Taken For Safety Reasons, Changes To Reference Safety Information, Patient Exposure, And Presentation Of Individual Case Histories

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Poor quality reports: poor documentation of ADR reports or insufficient information provided to perform a thorough assessment in the Presentation of Individual Case Histories section, non-assessment or poor-assessment of new safety signals in the Overall Safety Information section, failure to highlight misuse, absence of standardized medical terminology (e.g., Medical Dictionary of Regulatory Activities [MedDRA])

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Changes have been made to the Company Core Data Sheet (CCDS) since the submission of the last PSR and the covering letter does not highlight the differences between the CCDS and the European Union or National SPCs

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Failure to address previous requests from HAs (e.g., close monitoring of specific safety issues).¹

The MAHs are accustomed to establishing robust procedures and systems to support compliance with the PV regulations set forth by regulatory bodies around the globe; however, it is also important that their business partner/s are also compliant in meeting the regulatory submission timelines.

The Safety Data Exchange Agreement (SDEA) among the pharmaceutical companies defines the distribution timelines. The business partner/s are required to submit the ADRs as individual cases or aggregate data within the required timelines as part of the global and local regulatory obligations and to meet the clauses presented in the SDEA. With the current challenges in meeting the regulatory/business partner timeline compliance, newer and focused approaches are paramount for the pharmaceutical companies. Business partner timelines are monitored during the receipt of ICSRs and submission of the ICSRs back to the business partner within the agreed timelines as per the SDEA.

In the event of noncompliance, regulatory action may include the following:

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HAs may issue a formal warning reminding the MAHs of their PV regulatory obligations

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Noncompliant MAHs may be inspected to determine the extent of noncompliance and then re-inspected to ensure compliance is achieved

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Cases of serious or persistent noncompliance may be prosecuted¹

Challenges in PV Compliance

The current challenges faced during the monitoring of PV compliance are as follows:

Increasing volumes of AE data with time

Over time there has been an increase in the volume, type, and source of safety data collected during the life cycle of the product. This has resulted in the need for diversified systems to capture and store this information. Furthermore, the current landscape has evolved into a globalized and highly decentralized environment, challenging existing systems, data storage, monitoring, and auditing. Companies must develop more reliable, proactive, and easy follow-up systems for managing and tracking data received from various sources of spontaneous reports, clinical trials, other solicited reports, literature publications, patient support programs, market research studies, and HA reports including EMA EudraVigilance database.

Changing regulatory requirements

Compliance with the latest regulations such as the E2B (R3) and Identification of Medicinal Products are in the various stages of being mandated across different International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) regions. Business growth into new markets necessitates the PV systems and processes to scale smoothly and sufficiently. Ensuring that existing PV systems and applications constantly evolve to support the business effectively is an important requirement. These evolving regulations affect PV operations at multiple levels and many have fundamental implications for the underlying database structure, configurability, reporting capability, and integration with other systems and data sources. Inadequate support for novel and evolving regulations can result in potential regulatory noncompliance and associated penalties. In addition, reporting in the non-ICH regions is even more challenging as the requirements vary more widely than among ICH countries.

System integration, reliability, scalability

Some of the key challenges faced by the PV-IT support include issues associated with the integration of applications and sharing of data between siloed applications as well as availability and scalability of applications. Poor scaling and performance issues lead to system breakdowns resulting in unavailability of mission-critical systems to business users thereby affecting business. Lack of application integration warrants manual intervention, which can result in data inconsistencies and inefficiencies. Moreover, many of the legacy systems are typically not up to date with the latest IT technologies and standards. This can result in potential data security and privacy issues. Managing IT vendor relationships, especially with non-responsive vendors, can be another challenge with stretched timelines for implementation of new features, forcing PV teams to figure manual workarounds or use external consultants for customizations - resulting in expensive and unmanageable systems.

Future Considerations for PV Compliance

Transforming PV compliance

Tracking implementation status, gathering and interpreting data, and working across boundaries are key pharmaceutical compliance activities that impact multiple functions, from risk management planning to vendor relationships. Many organizations use generic tools to manage PV compliance-related activities. They track the large volume of data using the following three methods:

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Use of emails/ Excel spreadsheets/ SharePoint

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Customized in-house tracking systems

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External systems for tracking

Many organizations do not have an efficient or scalable tracking system and may lack a single source of truth for compliance information.³ Tracking compliance could take up a significant amount of time and, in some cases, can go up to 50% of overall team time of PV operations.

Automation will be critical to the success of the pharma industry

Within PV and regulatory compliance, pharma companies are constantly dealing with a growing influx of changes – more data from more sources, more products in more locations, and constantly changing reporting requirements. Each change has a cascading impact on other parts of the organization. Businesses need Regulatory Information Management and PV orchestration tools supported by knowledgeable technology partners, who can understand the industry and help companies include and make sense of massive amounts of data while also navigating a complex and ever-evolving regulatory environment. The MAH is actively looking for ways to reduce the growing PV costs and lower the possibility of human errors in PV tasks.⁴ Automation is a vital element that can help businesses to achieve both goals through the use of tools that help in achieving the following points:

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Making end-to-end safety processes leaner

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Manage volume fluctuations, specifically during volume spikes (e.g., legal batch cases)

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Enabling appropriate prioritization based on regulatory timelines

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Eliminating redundant steps in existing process

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Boosting team's efficiency

As regulatory bodies introduce new tools to collect and evaluate AEs, there are increasing opportunities for MAHs to integrate automation into their everyday PV processes.⁵

Manpower alone cannot manage the increasing data volumes and complexities. This is where technology solutions will become mission-critical⁴

Technology will support PV and regulatory compliance processes in ways that were not comprehensible a decade ago, which will be vital to the success of all pharma companies. There are not enough people with sufficient skills and bandwidth to manage all the data that needs to be processed, sorted, and shared. Technology will support the evolution of the structure of the pharma industry workforce and changing roles within the industry.

PV tools will be re-examined ⁴

Expect that more than 80% of the top 100 pharma companies will initiate a re-examination of their safety platforms and supporting technologies in the next few years. This is due to the increased volume of AEs and pressure from businesses to lower their costs through automation process. The vast majority of the top 100 to 200 pharma companies will engage in automation projects. The industry is recognizing their aged, inflexible technology cannot meet the growing needs of the business.⁴

In order to tackle the above challenges faced in the tracking of enormous amount of data received, a tailored tracking software is needed for the following purposes:

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Provides access to multiple stakeholders

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Ensure audit and inspection readiness including validated (Title 21 CFR Part 11)

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Proactively notifies all users when key information is updated

To transform PV and reduce the complexity of compliance operations, pharmaceutical organizations should perform the following activities:

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Audit organization's current approach to compliance tracking, reporting, and collaboration to identify gaps, redundancies, and risks

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Advocate for investments in tailored software solutions that can simplify compliance-related activities, increase productivity, and improve visibility across the organization.

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Better alignment between label database and PV database for a seamless flow of information in a timely manner upon new revisions or updates to the labeling documents and vice versa

Conclusion

The conventional approaches in monitoring PV compliance have been challenging to manage as they require a lot of manpower. It also leads to huge turnaround time. Automating this space is expected to produce better results around visibility, accessibility, data accuracy, with reduced resource dependability. Automation is likely to reduce effort by more than 80% and decrease cost by at least 50%. At the same time, it will improve the accuracy, quality, and consistency of AE data.⁶