Pharma Buoyed By Preview Of 'Helpful Changes' To EMA's Signal Management Guide
Executive Summary
The European Medicines Agency is revising its signal management guideline to clarify several terminologies and offer flexibility to help companies comply with their legal obligation to monitor the revamped EudraVigilance database. The biggest relief for the industry is that the new procedures in the guideline will be initially tested on a small number of products.
The EU pharmaceutical industry, which has seen a revised draft of the European Medicines Agency's keenly-awaited guideline on how drug companies should use the revamped EU pharmacovigilance database to support their signal management activities, appears to be pleased with some of the clarifications and flexibility being offered in the document. It is hoping that these "helpful changes" will make it into the final version of the guideline, which is expected to be published later this month ahead of the EudraVigilance database going live on Nov. 22.
The EMA's signal management guideline, otherwise known as Module IX of the agency's collection of good pharmacovigilance guidelines (GVPs), will introduce major procedural changes for industry when it is finalized. The document will explain how companies should comply with their new legal obligation to continuously monitor the updated EudraVigilance database and report validated signals within strict timelines. (Also see "EudraVigilance Update Needs 10-Day IT Shutdown At EMA; Interim ADR Reporting Plans In Place" - Pink Sheet, 8 Oct, 2017.)
The initial version of draft of the guideline had drawn major concern from the industry when it was released in Aug. 2016 as it appeared to assign a somewhat "diminished" role to marketing authorization holders (MAHs) in this pivotal process. (Also see "Pharma Firms Fear Diminished Role In Revised EU Signal Detection Guideline" - Pink Sheet, 14 Nov, 2016.) The EMA subsequently agreed to address industry's concerns, saying it was taking into account the “constructive and pragmatic” feedback it had received following a public consultation on the draft guideline. (Also see "EMA To Address Industry Concerns in Revised Signal Management Guideline" - Pink Sheet, 27 Jan, 2017.)
The EMA recently shared a second draft of the guideline with the industry, Sue Rees, executive director for global patient safety & labeling at Amgen, told delegates at a conference in London last week*. The new draft offers greater clarity on what qualifies as an "emerging safety issue", and provides better insight into crucial terminologies such as "signal management" and "signal confirmation," Rees commented. It also supports a more risk-based approach when it comes to deciding how frequently the EudraVigilance database should be monitored. Rees is hoping these changes will be retained in the final version of the guideline.
On the other hand, Rees thinks that the revised guideline is "still very unclear" and "confusing" about the process that companies should follow to notify validated signals. She is hoping that this too will be addressed in the final version.
Some of the notable changes in the updated draft guideline were highlighted during the conference. These pertain to:
Emerging safety issues: There is greater clarity on what qualifies as an "emerging safety issue" so that MAHs do not saturate the system with the transmission of less urgent information. The updated guideline states that MAHs should only communicate those safety concerns as emerging safety issues, whose urgency and seriousness cannot permit any delay in handling.
An emerging safety issue refers to safety concerns for which "you would drop everything in order to address it" – Sabine Straus, Medicines Evaluation Board
Emerging safety issues should be "limited to real serious issues" that require urgent regulatory attention because of their potential major impact on the benefit-risk balance of a product and/or on patient or public health, Sabine Straus, a member of the EMA's pharmacovigilance committee, the PRAC, said at the same conference.
Straus, who also works for the Netherlands' Medicines Evaluation Board, said the EMA had seen an example of a generics company labeling "pancreatitis" as an emerging safety issue because this was included in the generic product's summary of product characteristics (SmPC) but not in the originator's SmPC. "This is not an emerging safety issue," she said. An emerging safety issue, she explained, referred to safety concerns for which "you would drop everything in order to address it," which means that only a very limited number of issues would meet this criterion.
Straus clarified that while most requirements in the GVP IX pertain to handling safety concerns that are detected during the monitoring of EudraVigilance, the requirement on timely reporting of emerging safety issues applies to "all sources of information," – including information from clinical trials, literature, the company's own database, etc. Companies are required to inform the EMA/national competent authorities (NCAs) of emerging safety issues within three working days.
Alternative processes and terminologies: The revised guideline importantly recognizes that "individual organizations may follow alternative signal management processes and terminology" that encompasses the general principles outlined in GVP IX, according to Rees, who is also the EU qualified person for pharmacovigilance (QPPV) at Amgen.
Rees believes this is an important clarification. It means that regulators "are not expecting companies to change everything that they do" but wants them to follow the general principles outlined in the guideline, she said. Rather than getting hung up on "we call it this, and you call it that," Rees said the revised guideline clarifies that such arguments do not matter as long as one follows the general principles in the document.
Straus said while it would be easy to draw a flowchart for signal detection and management following a "nice, sequential and logical order," anybody involved in the process would know that "it doesn't work like this." In terms of syncing their signal management processes and terminologies with the GVP IX, Straus said the NCAs faced the same kinds of issues as MAHs.
This, she explained, is because some EU member states "have a very mature system in place" for handling signals. In the Netherlands, for example, there is a separate signal detection agency (Lareb) that sifts through a lot of information and identifies whether it constitutes a real signal. As such, before an issue is brought to the MEB, a lot of work has already been done, she said.
All NCAs and MAHs "have a certain way of working" and "that's fine" as long as the signals brought forward are in line with the principles of the GVP IX, Straus added.
She explained that in the revised guideline, the EMA had addressed all aspects of the process – i.e., signal detection, validation, confirmation, analysis/prioritization, assessment and recommendation for regulatory action – in light of the requirements of the EudraVigilance implementing regulation (No 520/2012). "As you can imagine, [signal] prioritization is a difficult one to address only after validation, but that's the way that the legislation is written," she said.
Signal validation: Rees said that "signal validation" was currently a hot topic in her company because a lot of requirements are triggered when a signal is considered validated. While the guideline describes signal validation as the process of evaluating the data supporting a detected signal to justify its further analysis, Rees believes that among companies, "there is a varying understanding of what validation means."
The revised guideline, she noted, helpfully clarifies that the "extent of evaluation performed during signal validation versus further analysis may vary" as per an organization's internal procedures. This provides greater flexibility for companies to address signal validation in accordance with their procedures, she added.
Signal confirmation: While terms like signal detection and validation are well known, Straus said there was confusion around what constitutes "signal confirmation."
Signal confirmation, she clarified, refers to a regulatory step under which validated signals are submitted for an EU-level discussion by the PRAC rapporteur or the lead member state, and does not mean that there is a causal relationship.
"It is just a regulatory step to bring a signal to PRAC to have it discussed at the European level… This is a different kind of confirmation that we need to have within the [work]flow of signal management" due to the requirements of the implementing legislation, she explained.
Monitoring frequency: The revised guideline allows companies to be flexible and use a risk-based approach when determining how frequently they should monitor EudraVigilance data, but it specifies that this should be done at least every six months. This is a major change from the original proposal, which required the database to be checked every two weeks for products under additional monitoring, and every month for all other products.
For very old products that tend not to generate safety data, industry had requested that they should only be monitored annually. But this suggestion was not accepted by the EMA, Straus remarked.
An Opportunity And A Challenge
While opening up the EudraVigilance database to MAHs is an opportunity to support public health, Straus believes this initiative also presents challenges.
"Sometimes a detailed legislation can be a blessing and sometimes it can cause additional challenges," she said, adding that in this case all stakeholders worked together to make the best of their legal obligations and make the new system work as best as possible to better protect public health.
Regarding concerns about duplication of work because MAHs and NCAs would essentially be looking at the same data in EudraVigilance, Straus said the issue had been discussed internally "and we have tried to come up with good solutions." The aim has been to ensure that MAHs and NCAs look at the same data differently.
One-Year Pilot
Rees said the industry was "delighted" by the EMA’s announcement in August that the new procedures outlined in the GVP IX were going to be tested in a one-year pilot that would only cover products that have a black triangle (ie, are subjected to additional monitoring). The pilot is due to star in February 2018. (Also see "EMA Pilot To Help Companies ‘Ease In’ To New EudraVigilance System" - Pink Sheet, 11 Aug, 2017.)
The pilot "really has been a big relief for a lot of people" as companies "will have a bit more time to think about things" while the new procedures are tested on a smaller number of products,” she said.
Based on the experience from the pilot, the GVP IX may need be revised again or it may be that "everything goes very smoothly, and we are able to implement it for all substances," Straus added.
*Sue Rees and Sabine Straus were speaking at the 11th Drug Information Association (DIA) forum for EU qualified persons for pharmacovigilance (QPPV), in London, on Oct. 4 – 5, 2017.
From the editors of Scrip Regulatory Affairs.