Abstract
Background to MHRA pharmacovigilance inspections
In 2003, a statutory national pharmacovigilance inspection programme was initiated by the Medicines and Healthcare products Regulatory Agency (MHRA). This programme was expanded by the introduction of the concept of supervisory authority inspections with the updated legislation in 2012. 1 This mandated that the MHRA must inspect marketing authorization holders (MAH) with centrally authorized products that had located the pharmacovigilance system master file (PSMF) in the UK, against the pharmacovigilance requirements laid down in Titles IX and XI of Directive 2001/83/EC as amended 2 (‘the Directive’), on behalf of the European Medicines Agency (EMA).
Pharmacovigilance inspections fulfil the legal obligations of the MHRA as a national competent authority, in accordance with Article 111 of the Directive, ‘to ensure that the legal requirements governing medicinal products are complied with, by means of inspections’. In this role as the supervisory authority for some pharmacovigilance systems in the EU, the MHRA conducts pharmacovigilance inspections of companies with centrally authorized products, according to the EMA’s schedule, 3 in addition to inspections requested by the EMA’s Committee for Medicinal Products for Human use (CHMP).
The legal basis for inspections is supported by national legislation in the UK, the Human Medicines Regulations 2012 as amended (HMR), 4 which confer powers of inspection to the MHRA as the enforcement agency, to fulfil the responsibilities of a national competent authority in Article 111 of the Directive.
In light of the UK’s approaching departure from the EU, the government would prefer to leave with a deal, but is committed to preparing for the outcome should it not be possible to reach a deal. Depending on the outcome of the UK’s departure from the EU, the MHRA’s interaction with the European medicines regulatory network, including the sharing of inspection outcomes, could change. However, the MHRA will continue to conduct risk-based pharmacovigilance inspections of organizations holding UK marketing authorizations.
Objectives and opportunities from inspections
One of the primary objectives of pharmacovigilance inspections is to verify compliance with the provisions in Title IX of the Directive and HMR Part 11. During an inspection, inspectors can review source documentation and data to verify the completeness and accuracy of data submitted to authorities to support decisions made in benefit/risk assessments. This is critical for ensuring that patients are protected through sound decision making by the competent authorities.
In addition, inspections give the MHRA the opportunity to educate MAHs with less mature pharmacovigilance systems and help them better understand the requirements. From their position, inspectors can identify areas where further guidance or changes to legislation may be required, and this perspective has been added to the MHRA’s contributions to European legislation and guidance documents as part of the European Inspector’s Working Group. In addition, the MHRA routinely communicates important messages through symposia, annual metrics reports, and blog posts on its website.
Finally, as the MHRA typically discovers during re-inspections of companies, inspections help to improve compliance across the industry, which in turn ensures that the rights, well-being, and safety of patients are better protected. The MHRA aims for a collaborative approach with the organizations inspected and works together with organizations during inspection closure, to agree corrective and preventative action plans that will effectively address the non-compliances observed and bring the pharmacovigilance system into compliance.
Recent challenges
Between the financial years, 2016–17 and 2017–18, the number of organizations subject to MHRA pharmacovigilance inspections dropped by 40% from 37 to 22 (Figure 1). This is a marked decrease in the number of organizations inspected. However, the total combined number of days spent inspecting by accredited MHRA pharmacovigilance inspectors in 2017–18 was slightly higher, with 270 days spent inspecting, compared with 259.5 days in 2016–17.
Number of inspections per year compared with median days* spent per inspection over the years1.
One factor that affects the number of inspections the Good Pharmacovigilance Practice (GPvP) inspectorate can conduct in a year is the availability of inspectors. This was not the case between the financial years 2016-17 and 2017-18, and it appears that the recent reduction in the number of inspections was caused by an increasing number of days being spent per inspection. The inspection days represented in Figure 1 might be spent all on site or could comprise some planned inspection time conducted remotely prior to the inspection, or unplanned inspection activities conducted remotely after the inspection to complete the review of inspection documentation.
With fewer inspections being carried out, the inspection coverage of the pharmacovigilance systems for UK authorized products has reduced, and it follows that the objectives and benefits presented previously may not be fully realized. The challenge of ensuring adequate supervisory coverage of pharmacovigilance systems leads the MHRA to further consider how inspection work can be prioritized appropriately, with the aim of improving patient safety through the promotion of industry-wide compliance.
The resources available to conduct pharmacovigilance inspections at the MHRA is not unlimited and, therefore, in line with GPvP Module III, 5 a risk-based approach is used to identify and prioritize pharmacovigilance systems for inspection. As the focus of the inspection programme has increasingly been directed towards higher risk organizations, almost all of the inspections that are routinely conducted are becoming more complicated in nature. As a result, the duration of inspections has increased. These inspections cover complex pharmacovigilance systems with multifaceted topics to review including:
(1) Products that have unique and detailed requirements such as additional pharmacovigilance activities, including post-authorization safety studies, and additional risk minimization measures such as the distribution of educational materials for patients and prescribers.
(2) Organizations that have undergone significant mergers or acquisitions, or have acquired licences for significant volumes of products, which broadens the inspection scope to cover aspects such as data migration and complicated arrangements with global partners.
(3) Large organizations where it can take time to navigate the pharmacovigilance system and understand the processes in place, often with a complex network of partners, affiliates and research or commercial interests.
To deal with the challenge of increasing days expended for each organization inspected, the approach of the MHRA’s GPvP inspectorate has been changing, with new elements being incorporated into the inspection programme to increase its supervisory capability.
New inspection approaches
A clear answer to reducing the number of days spent conducting an inspection, and consequently increase the MHRA’s coverage of organizations within the inspection universe, is to reduce the scope of individual inspections. This has seen the introduction of more targeted inspections where the focus is on pharmacovigilance processes considered to be of the highest risk for each pharmacovigilance system, in contrast with reviewing the full system. This approach has also been used to cover larger pharmacovigilance systems across multiple inspections, meaning that very large organizations could see more frequent inspections.
A less accounted for factor that can increase the duration of inspection occurs when organizations do not provide documentation in a timely manner or provide inaccurate information to the inspectors. The metrics report published in December 2018 covering the financial year 2017–18 6 highlighted the number of major findings related to deficiencies in the provision of information to enable supervision by national competent authorities, including via inspection, which made up 16% of all major findings in the reporting period, as well as being part of one of the four critical findings reported in the period. These findings are largely in relation to the provision of incomplete and inaccurate information via the eXtended EudraVigilance medicinal product dictionary (XEVMPD) and in the PSMF, both of which are used extensively in inspection planning and can contribute to the addition of unplanned inspection days. It is hoped that by highlighting this common area of non-compliance, the quality and accuracy of these information sources will improve so that inspections can be appropriately planned based on complete and accurate information, including the necessary duration and resource.
Another means to increase the GPvP inspectorate’s supervisory capacity is the use of office-based days combined with an on-site inspection. This allows the inspectorate a degree of flexibility in providing time for a planned review of extensive pre-inspection documentation before the on-site days or, where necessary, to complete the review of outstanding inspection documentation after the planned days on-site. Alternatively, conducting entire inspections remotely is a further mechanism the inspectorate can use to verify the compliance of organizations. This involves the review of pharmacovigilance activities for a specific product or product class and could include single or multiple MAHs in its scope. These remote activities are considered to be an inspection activity and may result in an on-site inspection, but in the first instance should require lower levels of input from the inspected MAH(s).
Compliance management outside of inspections
One of the objectives of the MHRA inspection programme is to promote industry-wide compliance, and the GPvP inspectorate has developed a number of mechanisms to achieve this. One of these is the formal compliance management process. This is an internal forum for reviewing known or suspected incidences of non-compliance with pharmacovigilance obligations and deciding how this will be managed. As part of this, MAHs can be approached by the inspectorate to provide information to resolve or clarify issues that have been raised through referrals or other risk assessment work. This is not considered to be an inspection. However, inspections can be triggered as a result of compliance management activities.
In addition, where non-compliance is identified with a service provider during an inspection of an MAH, the GPvP inspectorate will request client-wide remediation by the service provider in the form of an impact assessment and comprehensive corrective and preventative actions. By requesting this client-wide remediation from the service provider, compliance can be promoted beyond the originally inspected MAH, and potentially without the need to trigger inspections of other clients of the service provider.
Summary
In summary, the MHRA pharmacovigilance inspection programme applies a risk-based app-roach to scheduling. Consequently, most of the inspections conducted are of high-risk pharmacovigilance systems that are large or complex in nature or include high-risk products with additional pharmacovigilance activities and additional risk minimization measures in place to manage known risks. This additional complexity is increasing the duration of inspections and, as a result, reducing the capacity for the number of organizations that can be inspected by the MHRA in any given year. Therefore, the MHRA continues to consider the ways in which it can promote and protect public health by ensuring regulatory compliance through inspections and working with companies to resolve identified deficiencies.
