A Beginner’s Guide to Safety Reporting in Clinical Trials

By William Ray - Drug Safety Expert

So, you’ve managed to work your way into a role in drug safety and you’ve started with your case processing - you’ve even created a Council for International Organizations of Medical Sciences (CIOMS) form. But do you know what happens next with the distribution of the case? I’ve come across quite a few people who know a great deal about pharmacovigilance (PV) but have less of an idea of what happens when it comes to the distribution of cases and beyond. It’s useful to know and is an important step.

“What is the process then?”, I hear you ask. “You just send an email, right?” Well, I’m getting to that! I am going to describe the process for clinical trials as this is what I am most familiar with, but there are similar processes for post marketing too.

Classification of reports

There are a few things we need to know about the classification of case reports before we go any further. There are many types of report that are received and generated throughout clinical trials, with their own associated reporting requirements and formats. In general, report types in clinical trials can be split into two categories: expedited and periodic.

Expedited Reports

The bread-and-butter of clinical trial PV is the receipt and processing of serious adverse events (SAEs). Certain SAEs will require expedited reporting to regulatory authorities (RAs), ethics committees (ECs) and investigators involved in the study. For example, Suspected Unexpected Serious Adverse Reactions (SUSARs), would routinely require reporting. Some non-SUSAR ICSRs which, nonetheless, are considered to affect the benefit-risk balance of a study may also require reporting in an expedited manner.

Periodic Reports

Periodic reports can also be termed aggregate reports and contain grouped information to be submitted at defined intervals, rather than triggered by specific events. Periodic reports include annual Development Safety Update Reports (DSURs) or more simple line listings of SAEs or serious adverse reactions (SARs). For both expedited and periodic reporting, requirements can differ from territory to territory, so robust regulatory intelligence is a must, along with internal processes that ensure all ICSRs are suitably assessed, and periodic reports scheduled. Even within European Medicines Agency members, there are differences in reporting requirements for SUSARs: some RAs wanting all SUSARs from within the trial and others only wanting to be made aware of ones occurring in their country. This also highlights not just the need for external regulatory intelligence, but also for PV to be fully integrated into the sponsor clinical trial team, so PV is fully aware of all the countries that a study is operating in. Along with being able to accurately identify what reports are required for submission, companies should also be aware of timelines and where they may differ from industry ‘norms’ (i.e. a 15 day SUSAR to be reported to the US FDA requires submission within 14 days to Argentina). Finally, at this stage, sponsors will need to identify if there are any additions needed to the report to meet local reporting requirements. For example, SUSARs reported to the US FDA will also need an accompanying analysis of similar events (AOSE) and those occurring in Spain require the case narrative to be translated into Spanish for the submission to the Spanish RA. Where studies are blinded, there will usually be the need to unblind ICSRs before reporting, so there not only needs to be a level of regulatory intelligence to identify which parties may be the exception to this rule, but also internal processes to ensure no inadvertent unblinding of other study team members or investigators. Submission methods for reports Once a report has been identified for submission, along

with the required recipients, the next step is to know HOW to send the report. Distribution can be via gateway, email, fax, courier and/or hand delivered by a company representative. So, we can see this is already getting a bit more complicated than just sending an email. Quite often there are also supporting forms. Web portals can add their own layer of complexity, ranging from the ‘simple’ and accessible UK eSUSAR tool to the Spanish portal, which can only be accessed by someone resident in Spain, or even the EMA EudraVigilance portal, which requires a two-day training course to become a certified user. Again, this highlights the need for PV to be properly integrated and informed of study decisions, so any set-up of portals can be coordinated in advance of reports requiring submission.

Safety Information flow

Below is a diagram outlining the process followed by each report as it is distributed and followed up for compliance purposes. An interesting scenario often encountered when working with a suite of trials is cross reporting. This is when reports about the same medicinal product, but different manufacturer, need reporting. In this instance, an agreement between the Marketing Authorisation Holders (MAHs) is required to say who will report such cases. Unfortunately, it is too simple to say that all reports should be reported to RAs or ECs in each trial. This will be dependent on the regulatory intelligence for each party to the level of whether they would like to receive reports from a specific trial, or all reports available across a development programme. This leads me on to the subject of under- and over- reporting. Under-reporting is serious. If a report to an RA is missed this can result in action from the RA. Over-reporting is also a problem. If an RA is flooded with unwanted reports, they will not be happy about it. Under-

Report unblinded, if necessary, and finalised Report triaged using regulatory intelligence Report distributed based on regulatory intelligence with supporting information and webforms Acknowledgements collected for compliance of submission

Figure 1: safety reporting submission flow As you can see, assimilating all the regulatory intelligence for a given clinical trial and then for a given report can be very complex, especially when there are a lot of countries involved, as is often the case for large clinical trials. Though that being said, rule-based computer systems are being developed that take a lot of the heavy lifting out of the decision making, distribution and compliance metrics. Unfortunately, with these come other issues, such as balancing general rules that will function across a development programme vs study-specific requirements. I have seen both complex and simple systems used – some companies may simply opt for a spreadsheet and use of an email program like MS Outlook for the majority of their submissions. It depends on company preference. As described in the flow diagram, compliance also needs to be tracked after submission. With EudraVigilance, this will be with receipt of acknowledgement files. With distribution to other recipients, there are a range of methods that can be used to detect if a submission has been received and this depends on the systems being used. Compliance is important and if you are audited or reporting is often linked with subsequent inspections and - if you are a service provider - probably an audit from your client. This is just a brief outline of how safety reporting in clinical trials works and has not even considered maintaining safety data exchange agreements with partner companies. I’m sure you can understand that in the day-to-day activities of a safety associate that works in this area, there are many things to consider. There are often complex problems to solve and tight deadlines to meet.

William Ray

Drug Safety Expert