UK Regulator Promises Reasonable and Pragmatic Approach For EudraVigilance Inspections
Executive Summary
Aware that marketing authorization holders are still finding their way around the EU’s revamped pharmacovigilance database – a UK inspector explains what procedures and processes companies should have in place to show compliance with new requirements to monitor and report safety signals.
UK pharmacovigilance inspectors say that while they will take a pragmatic view when inspecting compliance with Europe’s new EudraVigilance database requirements, they expect drug companies to have put in place some "common sense" procedures and processes.
"As inspectors, we are very aware that people are going to be still finding their way,” the Medicines and Healthcare products Regulatory Agency’s Rory Littlebury said of the requirements to use the revamped database for signal detection purposes, which a number of companies have been required to perform since February 2018. (Also see "EU Regulator's Enthusiasm for Revamped Pharmacovigilance Database Tempered By Industry Concerns " - Pink Sheet, 27 Feb, 2018.)
The inspectors know that companies "are going to need some time to work out the processes to see what works, what is giving good information and what is giving false signals," noted Littlebury, an MHRA GPvP (good pharmacovigilance practice) inspector. Nevertheless, companies should have certain procedures and processes in place to show compliance, he said at the MHRA's 2018 Pharmacovigilance Symposium in London on May 3.
The improved EudraVigilance system is designed to make reporting easier for stakeholders and support stronger safety monitoring of medicines. It has also introduced new obligations for industry with respect to signal detection. Specifically, marketing authorization holders (MAHs) are now required to access EudraVigilance data and analyze electronic Reaction Monitoring Reports (eRMRs) for new signals periodically, and must report validated signals to the authorities within strict timeframes. (Also see "Enhanced EudraVigilance System Goes Live, EMA Updates Info For Users" - Pink Sheet, 22 Nov, 2017.)
As inspectors, we are very aware that people are going to be still finding their way - Rory Littlebury, good pharmacovigilance practice inspector, Medicines and Healthcare products Regulatory Agency
Inspectors are aware that companies dealing with the database are “working their way through the products in their portfolio, while dealing with a whole host of new data being made available to them," Littlebury said.
The new requirements are being tested in a year-long pilot by sponsors of around 300 active substances subject to additional monitoring; the pilot will end in February 2019. (Also see "Industry/EMA Discuss Early Concerns Over EU’s Safety Signal Reporting Pilot" - Pink Sheet, 9 May, 2018.) For companies facing a GPvP inspection during the pilot phase, Littlebury assured them that the UK inspectors would follow a reasonable approach.
The following highlights what the MHRA wants to see during an inspection of a company:
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- A documented methodology that shows how the MAH chose to review the eRMRs and decided on which events required validation: Littlebury said this would probably involve inspectors looking at the eRMRs and expecting the company staff to be able to "talk through the process" and explain how they "have gone from a spreadsheet with various numbers to [identifying safety] signals." The inspectors expect the company to be able to explain all the thinking behind their processes.
- A mechanism for documenting any changes to the review process: Littlebury said this was more relevant during the pilot phase as changes would have to be made if things do not go as planned. "All we want to see is whether you have documented what did work and what didn't, and whether you are documenting those changes at the end of a month or three months or on a month to month basis," he said.
- Evidence of how the MAH handles its signal management processes from other sources of information: The new levels of access to EudraVigilance data is just another source is just another source of information to help MAHs fulfil their obligations relating to signal management, Littlebury explained. The handling of the process from other data sources will also be inspected, he said.
- How provisions relating to quality management system (QMS) are applied: "I think this is fairly common sense at this point. We would be looking at decisions made in signal detection exercises, and would expect those decisions to be documented and made available for inspectors," he said.
- What consideration is given to additional QMS provisions: These include updating procedural documentation and staff training, which may also be inspected. Littlebury said staff training was a "big one" as there is a "whole list of technical information out there" that a company's technical staff should be familiar with.
Also speaking at the symposium was the MHRA’s Phil Tregunno, who acknowledged that the new database had resulted in "clear concerns" regarding the high volume of individual case safety reports (ICSRs) being generated and the possibility of duplicates being circulated within the EU regulatory system. (Also see "Pharma Frustrated With Revamped EudraVigilance Database" - Pink Sheet, 26 Feb, 2018.) This is one of the reasons why the pilot is being conducted so as to identify and address areas of concern, said Tregunno, interim group manager of the agency's Vigilance Intelligence and Research Group.
Tregunno stressed that MHRA inspectors do not want to make decisions that do not contribute towards public health. "My colleagues are in a listening mode and they are keen to adapt their inspection systems and processes based on the outcomes of the pilot," he said.
Tregunno also clarified some key areas of concern affecting the industry, such as in relation to recording ICSRs from signal detection in EudraVigilance. A common query on this front relates to what an MAH should do when it downloads an eRMR and decides to review a drug-event combination (DEC) of interest, but upon review of the line listings for the event realizes that there are new cases in the line listing that are not present in the MAH's safety database.
Tregunno said that such scenarios should be viewed in the context of the EU pharmacovigilance legislation that introduced the new EudraVigilance requirements. The aim of the legislation, he explained, was not to force companies to conduct an audit to validate the information in EudraVigilance with their own databases. "From a public health perspective, this is not a value-added activity," he said.
As per preliminary discussions within the EU regulatory network, Tregunno said there was, in principle, agreement that MAHs should not input such cases into their own databases. "The historical cases can be due to differences in [medical] practices at that point of time. We don't consider this [i.e., the addition of such cases to the company's database] to be a value-added activity for signal detection," he said. Some MAHs, however, may still choose to include these cases as they may have reporting obligations in other jurisdictions.
From the editors of Scrip Regulatory Affairs.