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The New Clinical Trial Directive, Low Risk Intervention Clinical Trials and Pharmacovigilance Reporting Adjustments

Posted on October 3rd, 2016 by in Pharmacovigilance


The new Clinical Trial Directive (EU 536/2014), is applicable since May 2016 with a transition period of three years (May 2019) for CT applications submitted before that date. Companies can still opt to stay with the previous Directive for any new submission until May 2017. This new Directive replaces the 2001/20/EC Directive and will add to a key Directive on GCP (2005/28/EC.)

Although a lot has been already posted about the impact of the new Directive on the ability for sponsors to implement clinical research programs in the European Union, it is worth looking at what impact it will have on safety reporting, especially in two specific situations (Urgent Safety Measures or USM, and Adverse Events reporting exemptions.)

Of note, if the initial 2001 Directive mentioned the word safety 9 times; the revised 2014 Directive used safety more than 100 times (though not all mentions are relevant to adverse events). This still says a lot about the growth in strategic and critical recognition of pharmacovigilance activities over the past 13 years, especially in the pre-marketing environment.

When unexpected safety information is likely to seriously affect the benefit-risk balance of the patients included in a trial, the sponsor and the investigator (usually the principal investigator) should take appropriate urgent safety measures to protect the subjects. Once these measures are implemented, the notification to Member States in the EU should occur no later than 7 (calendar) days after implementation. The previous Directive had no specific timeline. It is important to understand that USM differ from therapeutic decisions made by one investigator regarding a specific patient experiencing (or at risk of) an unfavorable event or outcome.

USM will be decided by both the sponsor and the principal investigator, and are applicable to all patients enrolled. USM will be decided after the review of findings from routine and non-routine safety signaling activities. Such findings could be one single but very concerning case (such as angioedema, hepatic injury, Steven Johnson Syndrome); a change in reporting rate of alarming serious adverse events; significant concerns coming from aggregate analysis of clinical trial programs; and/or non-clinical findings or a recommendation from a DSMB after review of safety data. These measures provide for the maintenance of the risk/benefit balance of the trial and the subject’s safety, sometimes at the cost of a study hold or discontinuation. While the type of findings listed here are not in the new EU CT Directive, the US FDA “new” IND rule (21CFR31.3(c)) gives excellent examples of what signal detection activities can consist of. It is interesting to see how a combined reading of the US and EU regulations provides sponsors with all the tools sponsors need to implement in order to fulfill their commitment and obligations on patient safety.

Another document derivative from this new EU Directive is a draft being circulated about a risk proportionate approach for low intervention clinical trials (LICTs). As per the proposed draft, LICTs meet the following criteria:

  • Investigational Medicinal Products (IMPs) that are already authorized
  • IMPs that are used within the approved label terms or in alignment with evidence-based and scientific literature support
  • The study protocol does not pose more than minimal additional risk or burden to the safety of subjects compared to approved uses.

For these LICTs, adaptions to adverse event recording, collection, and reporting are possible and should be detailed in the risk assessment and mitigation plan that sponsors should generate in conjunction with the protocol development, to be approved by the Health Authorities. It will help clarify what to do and report for Post-Authorization Safety Studies, which often meet these low intervention criteria, and will simplify what is sometimes the administrative burden of reporting AEs.

This adaptation of reporting rules is in fact also possible for trials others than LICTs.  Article 41 of the new Directive gives the possibility for the investigator to not report on an expedited basis certain serious adverse events to the sponsor, if provided for in the protocol. A good example is when trials involve specific population/diseases combinations where efficacy or safety endpoints meet the criteria of serious adverse events. These events will still have to be reviewed by the sponsor and the DSMB for signal detection purpose.

Even if this Directive will only be fully-implemented in 2018, it should give sponsors the opportunity to adjust the SUSAR reporting rules in specific situations, making it more meaningful and relevant to the research objectives, while ensuring optimal patient safety.

J.P. Clement


The scope of what pharmacovigilance leaders must consider has greatly increased as regulatory agencies worldwide have broadened their expectations from pharmaceutical companies. The pharmacovigilance department must know about activities beyond their direct influence, including information about product licensing, out-of-stock situations and quality control systems. This means that their activities must cover the whole life cycle of medicinal products, coordinating their efforts with clinical and medical affairs, and contacting all local affiliates.   Download our complimentary white paper that addresses the challenges posed by the expectation for global oversight of the end-to-end medicinal product life cycle, and that proposes some fundamental steps that should be taken by pharmacovigilance leaders.

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All opinions shared in this post are the author’s own.

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