When pharmacovigilance specialists consider regulatory submissions, they usually focus on the PSUR, RMP, or DSUR. But one document quietly plays a pivotal role in benefit-risk evaluation during variation procedures and referral assessments: the Addendum to the Clinical Overview (ACO).

At first glance, the ACO is just another document. But dig deeper, and it’s a powerful tool for shaping regulatory opinion, influencing safety-related changes, and demonstrating proactive pharmacovigilance. And it’s not just for regulatory affairs – pharmacovigilance specialists should pay close attention to its contents.

What Is the Addendum to the Clinical Overview?

An Addendum to the Clinical Overview (ACO) is a key document submitted during the renewal of a marketing authorisation for a medicinal product. It critically evaluates all safety and efficacy data gathered since the initial approval or last renewal. The main goal is to reassess the product’s benefit–risk profile based on new clinical experience, real-world use, and pharmacovigilance findings.

The ACO is a comprehensive update to confirm that the product remains safe and effective for continued use. It helps regulatory authorities determine whether the marketing authorisation can be renewed – typically for an unlimited period – or if further review is required. The document must reflect current scientific knowledge and confirm that product information remains accurate and up to date. As part of the authorisation dossier, the ACO protects patient safety and maintains regulatory compliance throughout the product’s lifecycle.

What Should the ACO Contain?

The first step in developing an Addendum to the Clinical Overview (ACO) is a thorough review of all data that could impact the benefit–risk balance. This includes Periodic Safety Update Reports (PSURs), regulatory actions taken since the last ACO, global marketing authorisation status, and relevant safety information such as emerging signals. In addition, safety experts must evaluate clinical trial data and post-marketing exposure worldwide to identify usage patterns. A summary of these patterns should be included. This comprehensive analysis forms the foundation of the Addendum.

Based on these findings, the safety expert must present a well-supported discussion explaining why the product remains safe and effective. The expert can justify the renewal of the marketing authorisation by demonstrating the absence of new risks or a positive benefit–risk ratio. The ACO thus serves as a critical document for evidence-based regulatory decision-making.

Addendum to the Clinical Overview Writing: Tell a Story, Not Just a Summary

Many ACOs fail because they read like technical checklists. But regulators are people, too – they want to understand the narrative behind the change.

Structure your Addendum to the Clinical Overview like this:

Background – What triggered the variation? Signal detection? Referral?

Evidence – Show your case: PV data, literature, clinical trials.

Impact – How does this affect the SmPC? The patient?

Conclusion – Reinforce the benefit-risk logic.

Keep it clear, concise, and well-argued.

ACO Tip: Don’t Underestimate Literature

A comprehensive literature review is an essential part of preparing a robust Addendum to the Clinical Overview. Many submissions fall short in this area, omitting key publications, case reports, or reviews that could reinforce (or challenge) the benefit-risk profile.

To streamline this process, use tools like the DrugCard Simple Search to quickly identify relevant published literature across multiple languages. At the same time, easy filtering by publication period and country helps narrow your search without missing important safety information.

This saves time and helps ensure no critical evidence is overlooked during the ACO preparation.

Final Thought: ACOs Deserve More Attention

In today’s regulatory environment, where safety concerns can lead to market withdrawals or restrictions, the ACO is not just a formality – it’s your chance to frame the safety narrative.

Pharmacovigilance teams should embrace their role in crafting a well-evidenced, persuasive ACO – and never forget the power of literature as part of the evidence base.

So next time you update a safety section, don’t just submit an Addendum to the Clinical Overview – make it count.