Regulatory Focus™ > News Articles > ICH Looks to Clarify 'Key Issues' With E2C Adverse Event Reporting Guideline

ICH Looks to Clarify 'Key Issues' With E2C Adverse Event Reporting Guideline

Posted 14 April 2014 | By Alexander Gaffney, RAC

In 2012, the International Conference on Harmonisation (ICH) released a new guideline, E2C (R2) - Periodic Benefit-Risk Evaluation Report, meant to ensure that PBRERs-standardized adverse event reports-contain the information regulators need to evaluate side effects and, if needed, take action.

Now ICH is out with an accompanying Question and Answer document on the E2C guideline, a document it says is intended to "clarify key issues" that have cropped up since the final release of the guideline.


ICH is an international group working to harmonize regulations across three main regions: the US, EU and Japan.

ICH's PBRER standard was first introduced in 1996, and has since been modified twice, first in 2003 and most recently in November 2012.

At its core, the PBRER is meant to allow regulators to be made aware of any emerging safety problems first encountered after a medicinal product has been approved for use by a regulator, or in quantities or effects greater than initially known.

"Like its predecessor, the Periodic Safety Update Report (PSUR), the harmonized PBRER is intended to promote a consistent approach to periodic postmarket safety reporting among the ICH regions and to enhance efficiency by reducing the number of reports generated for submission to the regulatory authorities," the US Food and Drug Administration (FDA) explained in April 2013.

As ICH explained, the guideline is also different from the earlier PSUR standard in that it "changed the focus from individual case safety reports to aggregate data evaluation."

FDA and other regulators are now in the process of implementing the new PBRER standard and phasing out other, non-harmonized adverse event reporting standards.

New Q&A

But since the guideline's release in 2012, ICH says it has become aware of "key issues" that require clarification.

Key among them: differing reporting intervals among regulatory regions. In the US, for example, PBRERs are due quarterly for the first several years after a medicine obtains marketing approval, and then annually thereafter. But companies rarely obtain marketing authorizations at the same time, meaning that the benefits of harmonization are lessened if they can't submit the same report.

ICH's advice to industry: Talk to regulators. ICH explained:

"In situations where the Marketing Authorization Holder (MAH) is preparing PBRERs on both a 6-month and an annual basis for different regulatory authorities, it is possible that a PBRER on a 6-month cycle could be submitted as an up-to-date PBRER containing 12-month interval data (to fulfil the second 6-month interval of an annual cycle). The same may be true if a product is on a 6-month cycle in one region and a 3-year cycle in another region. However, the MAH should always discuss the acceptability of this approach with the relevant regulatory authority or authorities, noting that this approach is not an attempt to amend local reporting periodicity, but rather an opportunity to use the 12-month document to fulfil the shorter reporting period requirement."

Elsewhere in the Q&A document, ICH expands upon another hot topic: Off-label use of a drug. PBRERs are meant to report on all uses of a drug, not just those uses which are on-label (i.e. used in accordance with the regulatory approval).

"Although the benefit-risk evaluation should be conducted across approved indications, it is critical that the risk assessment take into account all uses of the product," ICH wrote. Such data should be reflected in a company's discussion of a product's risk evaluation, ICH added.

The full Q&A document may be found online on ICH's website.

ICH Statement

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