News Updates

Background

Sponsors performing clinical trials in the EU must determine whether serious adverse reactions (SARs) to investigational medicinal products (IMPs) are expected, so that they can report suspected unexpected serious adverse reactions (SUSARs) within seven or 15 days as appropriate. Reference Safety Information (RSI) is a sponsor-generated document in the investigator brochure (IB) used for expectedness assessment; for EU-authorised IMPs, the SmPC can also be used for this purpose.

The RSI lists what the sponsor considers to be expected adverse drug reactions (ADRs) to an IMP at that point in time. Sponsor approaches to RSI development and use vary for a range of reasons:

• Sponsor process differences and the desire to maintain a single global approach per company
• Differences in national competent authority (NCA) RSI feedback and in company responses to this feedback
• Differences in disease conditions: For example, expectedness assessment against the background of disease-related events in oncology is usually more challenging than assessment of Stevens-Johnson syndrome (SJS), which is often clearly drug related.

The EMA is currently developing an EU Portal and database as well as other IT systems needed to implement the EU Clinical Trial Regulation (CTR). The EU CTR will go live in late 2018 and Article 44 states that EU Member States (MS) shall cooperate when assessing Drug Safety Update Reports (DSURs) and SUSARs, cooperation that will be facilitated by the following IT systems being built (or updated) by EMA:

• EudraVigilance Clinical Trials Module, the database sponsors use to report SUSARs
• SUR repository, the database into which sponsors will submit DSURs
• Collaborative MS workspace built into the IT system by EMA.

EU MS in the EU CTR comprise the National Competent Authorities (NCAs) and ethics committees (ECs). NCAs have been working under the Clinical Trial Facilitation Group (CTFG) to determine a process for cooperation in DSUR and SUSAR assessment. NCAs rapidly identified variability in RSI development as a cause of concern in harmonised safety reporting because it adversely impacts the quality of DSUR or SUSAR reporting and assessment. In response, EU NCAs increased their focus on RSI, resulting in increased RSI-related rejections when CTAs are submitted or IBs are updated. Sponsors have had to rapidly update approaches to avoid delays in clinical trial start-up as a result.

EU RSI Debate

There is widespread sponsor support of the above harmonisation objective. Unfortunately, although there is some guidance on RSI development in the Commission CT-3 guidance (extract below), this is open to interpretation, particularly the meaning of “frequency” and “nature”:

“If the RSI is contained in the IB, the IB should contain a clearly-identified section to this effect. This section should include information on the frequency and nature of the adverse reactions.”

EFPIA collated company feedback and identified the NCA RSI finding categories that caused confusion and/or problems for sponsors either due to NCA inconsistencies or because an aligned position was not facilitated with current guidance. These were:

Single Cases: Usually, a single ADR should not be included in the RSI because a robust aggregate analysis is required. This must be a case-by-case assessment, however, because some well-documented, classically drug-related single ADRs (such as SJS) could warrant inclusion. There was a lack of alignment on this last point.

Seriousness: ICH E2A clearly defines “seriousness,” but determining seriousness often requires medical judgement which may not be consistent across investigators. There is debate about whether it is appropriate to include a “serious ADR” category in the RSI, because RSI ADR inclusion is determined in aggregate, while seriousness is determined at an individual case level.

Non-Serious ADR: The CTFG RSI Q&A states that: “The content of the Reference Safety Information should include a list of all observed cumulative adverse reactions (i.e., related adverse events, AR).” Non-serious ADRs should therefore be included in RSI. Opinions as to whether these should be identified remain split because seriousness assessment is an individual case decision, whereas RSI ADR inclusion is determined in aggregate (consistent with the points above).

Severity: Severity categorization in the RSI may be possible in oncology and some specialized areas which use structured and objective common terminology criteria for adverse events (CTCAE) scoring, but in other areas severity assessments are usually highly subjective. They are also made at an individual case level. It is not always possible to assign a single severity score to an RSI ADR, as severity may range from mild to moderate to severe, especially for ADRs that reflect subjective symptoms. Determining whether ADR expectedness is due to severity requires medical/ scientific judgment and debate remains on the extent to which RSI can facilitate consistent assessment.

ADR Frequency: Should this be calculated based on all ADR occurrences (serious and non-serious, irrespective of causality assessment), consistent with SmPC frequency, or calculated only on ADRs causally assessed by the investigator/sponsor as “suspected ADRs” at an individual patient level? The latter is highly subjective and may underestimate frequency.

Further Complications: Some NCA require that CTA amendments, which include IB/RSI changes, must be approved before the RSI can be used. Determining when such a change is “approved” at an EU level is callenging, as the NCA approvals are received at different times. Coordinating these updates is particularly challenging for global clinical trials, and can also delay communication of important safety information to ECs, investigators, and patients.

Aligned RSI Approach

It is clear from recent interactions that NCAs and industry both agree that updating the CTFG RSI Q&As would be the most effective way to communicate consistent NCA expectations, drive sponsor harmonisation, and reduce RSI-based IB/CTA rejections. The CTFG has been working on updated Q&As which will hopefully bring clarity and drive consistency to the above issues, and we look forward to their publication in early 2017.

In the interim, sponsors should maintain an open dialogue with NCAs to ensure that decisions on including ADRs in the RSI, their presentation in the RSI, and the use of the RSI for expectedness assessment, can be clearly justified. Where possible, updating the RSI yearly, in alignment with the DSUR, may simplify maintenance of this information.

The focus on clinical trial safety will only increase as the 2018 EU CTR “go live” approaches. Further debate on these and other aspects must be expected. Bearing in mind that the ultimate aim of all changes must be to improve patient protection should ensure that the EU clinical trial safety monitoring framework is significantly enhanced when the CTR goes live in 2018.

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References available upon request.