Hello and welcome to Reference Safety Information II. Hopefully you will all have read my first Reference Safety Information (RSI) post which focused on how the RSI should be Identifiable, Approved and Consistent.
This post is a follow-up that will address some of the queries that have been received since the first post was published and give some further guidance on areas of confusion that were identified during my presentation at the recent GCP Symposium.
Some of you may be wondering why there is currently such a focus on RSI with this being the second post on the topic alongside it having been an agenda item at the last GCP Stakeholder Engagement Meeting (StEM) and both this year’s GCP and GPvP Symposia. Well the reason is that we are seeing major and critical findings relating to pharmacovigilance at the majority of inspections and the root cause for these finding is linked to the management of the RSI. These findings are being identified across all stakeholder groups, Commercial and Non-Commercial sponsors, Clinical Trials Units (CTUs) and Contract Research Organisations (CROs).
So what’s new? Having previously rambled on for nearly 1800 words what can I possibly have left to say about RSI? Well I think the best place to start will be at the beginning.
What is the RSI?
I’m starting here because the at the recent GCP Symposium the audience was asked the following question;
Is RSI defined in your quality system for Clinical Trials of IMP
3. Don’t know
On both days under 70% of participants answered with yes. So if it’s not clearly defined in your quality system is it fair to expect the staff that are using it or that are responsible for its maintenance to be able to do so in a compliant manner?
The answers to the following question also generated interesting results;
The purpose of the Reference Safety Information (RSI) is to clarify in one place the safety information of the IMP for investigators?
3. Don’t know
On both of the days over 80% of the participants answered this incorrectly with yes, this is not what the RSI is in a clinical trial.
The RSI in a clinical trial should be a list of medical events that defines which reactions are expected for the Investigational Medicinal Product (IMP). It will be one single definitive list or document that determines which Serious Adverse Reactions (SARs) require expedited reporting to the relevant National Competent Authority (in this case the MHRA) and which are exempt.
From a post marketing perspective the RSI is indeed all the relevant safety information relating to the product including the Investigators Brochure (IB) the Summary of Product Characteristics (SmPC) and the Core Data Sheet (CDS). The Guideline on Good Pharmacovigilance Practices (GVP), Module VII talks about RSI changes from a post marketing perspective but this is not applicable to clinical trials. So if you have staff conducting both post and pre marketing pharmacovigilance activities without a clear definition of the RSI, is it fair to expect them to able to operate in a complaint manner?
It’s not the Investigators Brochure or the Summary of Product Characteristics
It’s important to understand what I mean by this statement and think about how it affects your RSI processes. This RSI can be contained within the IB or SmPC but they are not one and the same. The IB is the IB and within it there may be a section that is being used as the RSI but this does not mean your IB and RSI are one and the same. The same applies for SmPCs, while a specific section of a specific version of a SmPC may contain your RSI they are not one and the same. This means that an approval to a new version of that SmPC for post-marketing use does not equate to an approval to change your trial’s RSI.
I’m making this point because the statement from my first RSI blog post appears to be causing confusion;
Just because a new one is released doesn’t mean you have to instantly use it as your RSI; the decision should be based on your documented risk assessment.
Now if you have working processes dictating that the RSI and IB or SmPC are one and the same then that statement will be confusing, but working with the understanding that they are independent then you can understand the point I’m making. Just because an IB or SmPC changes, it doesn’t mean your RSI has to change. However, remember any change to your RSI does constitute a substantial amendment meaning you cannot implement your new RSI and use it to assess expectedness until the amendment has been approved.
The following question was also asked at the symposium;
Who is responsible for approving the RSI?
1. Chief Investigator
3. Local Principal Investigators
4. IMP Manufacturer
5. Whoever is doing the expectedness assessment
The most popular option on both days was the Sponsor (65% or over on both days) followed by the Chief Investigator as a distant second (15% or lower). Yes I appreciate this was a trick question but it was still answered incorrectly by over 90% of participants on both days. The correct answer is “other”: the MHRA is responsible for approving the RSI, and until you receive that approval it should be treated as a proposed change and nothing more.
If you’re using a clearly defined section of the IB as your RSI and have important new safety information you want to communicate with your investigators there are other ways to do this outside of sending them an unapproved IB. A proposed change to the RSI is not urgent safety information, there is no guarantee that the proposed RSI change will be approved and so you cannot inform an investigator that a particular event is now associated with the IMP unless we agree with your assessment. If you want to make investigators aware that a particular event has been observed in study subjects there are other routes open to you such as sending out updated line listings or a dear doctor/investigator letter. It’s also worth remembering that you can add general new safety data that doesn’t impact on your trials risk to benefit ratio into other sections of your IB without a substantial amendment.
If a new version of the SmPC for your IMP is published this is different as it is does have a form of regulatory approval. This means there are no issues with the latest published SmPC being made available to your trial pharmacists, nurses or investigators as long as those conducting the expectedness assessment of potential SUSARs clearly understand which version should be used as the RSI (i.e. the version approved by the MHRA as part of the CTA, not a newly updated SmPC that has not been submitted as a substantial amendment) and are documenting it so that it can be reconstructed.
Remember there is no need to panic when it comes to your RSI. We appreciate it can be hard to coordinate for large multinational studies so a delay between approval and implementation whilst you collate all the global approvals and then implement it in one go across the study is totally acceptable. What’s not acceptable is implementation before regulatory approval has been given.
If you feel working with different RSI for different regions is the approach that will work best for you that’s fine, but there are two things you need to remember. Firstly, CT3 states that the most appropriate RSI should be used so make sure it’s clear what RSI you are using at any given time and why. Secondly if you are going to successfully identify all UK relevant SUSARs you will have to ensure all global SARs relating to the product that originated in clinical trials are assessed against the MHRA approved RSI not the RSI applicable in the SAR’s country of origin.
Yes, it can be complicated process and yes, there is currently a lot of focus on the area; but, I’d like to leave you with the following statement.
If you implement RSI without regulatory approval, then the regulator (MHRA) has not had the opportunity to:
- assess new information that may impact on the risk benefit ratio of your trial, and
- determine if as a result of the information your IMP and its dosing regime are still appropriate for your trial population.
Remember one of the Agency’s primary objectives is to protect public health and the SUSAR reports we receive that are dictated by the RSI play a key part in this.
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