The Investigator’s Brochure (IB) is a critical document in clinical research, summarizing the clinical and nonclinical data on an investigational drug product. As a living document, it must be regularly updated to reflect the most current information available. Leading an IB update requires input from a wide range of functional areas, including Chemistry, Manufacturing and Controls (CMC), nonclinical and clinical pharmacology, and pharmacovigilance. Strong project management and medical writing skills are essential to navigate the complexities of these updates.
When IB Updates Aren’t “Just” Updates
In some cases, sponsors may need to provide a detailed overview of changes made to the Investigator’s Brochure. Known as a “summary of change document” or SOC, this detailed report highlights edits using strikethrough and bold text to present before-and-after comparisons.
Importantly, the detailed SOC should not be confused with the high-level SOC typically included at the beginning of an IB. The process of creating a detailed SOC varies across organizations and can frequently become an afterthought, squeezed into the final days before the IB is due for submission to regulatory agencies, ethics committees, or investigators at clinical sites. In this blog, we’ll focus primarily on the detailed SOC.
Here are 5 tips to develop a detailed SOC without the last-minute stress:
1. Confirm Investigator’s Brochure Update Requirements Upfront
When updating an Investigator’s Brochure, one of the first considerations is whether a detailed SOC will be required. While many regulatory authorities accept a high-level summary of updates, certain situations call for a more detailed document. For example, the French National Agency for the Safety of Medicines and Health Products (ANSM) often requires detailed SOCs for clinical trials conducted in France, reflecting their stricter documentation standards.
A regulatory affairs representative plays a key role in identifying requirements, drawing on their experience with global health authorities and familiarity with region-specific expectations. This knowledge helps the team anticipate what will be needed and plan accordingly. Addressing requirements for a detailed SOC during the kickoff meeting lays the groundwork for efficient collaboration across functional areas like clinical operations, pharmacovigilance, and medical writing. The entire project team can align their efforts, allocate resources effectively, and maintain momentum throughout the IB updates.
2. Draft the SOC Alongside IB Updates
For a high-level SOC, the natural inclination might be to save it for last. However, this can lead to some frustration and wasted time later on. Consider instead drafting a high-level SOC alongside the revisions to the IB.
The high-level summary doesn’t need to include polished language or exhaustive specifics. Focus on capturing key updates as they happen, such as new nonclinical study results, revised pharmacokinetics data, or the addition of newly identified adverse drug reactions (ADRs). Documenting updates in real time reduces the risk of missed updates and eliminates the need to retrace steps. For example, if new safety data is provided, recording it immediately facilitates seamless collaboration with pharmacovigilance and other teams.
Using a high-level SOC as a dynamic tool simplifies the creation of the detailed SOC and keeps the project moving forward efficiently. It’s a small step that pays off significantly during finalization.
3. Align on Rationale
Medical writers often need to explain the rationale behind IB updates in a detailed SOC. For straightforward changes, this might simply mean stating, “new data became available.”Of course, not all updates are that clear-cut. For example, if a newly observed ADR is added to the Investigator’s Brochure, understanding the reasoning behind its inclusion—whether it was flagged by pharmacovigilance data, clinical observations, or regulatory feedback—is essential.
To avoid bottlenecks, allocate sufficient time for the team to collaborate on rationales for each substantial change. The high-level SOC serves as an excellent starting point for gathering input from functional leads. Engaging subject matter experts early ensures that each update is well-supported, with clearly defined reasoning that can carry forward to the detailed SOC.
Remember, the rationale isn’t just a regulatory formality—it adds important context that helps health authorities assess the implications of the changes. This clarity minimizes the risk of delays or queries during regulatory review.
4. Define Substantial Changes
While it is the sponsor’s responsibility to determine substantiality, collaboration among team members is vital. Agreement early on what qualifies as a substantial change and the rationale for the change helps streamline decisions and reduces the risk of confusion later in the process. The determination of a substantial update may not be possible at the kick-off meeting, it may come after a team review of the draft IB.
If any of the following questions can be answered with “yes”, then the revisions may be considered as substantial, and the detailed SOC may be prepared.
- Do the changes affect the safety of the clinical study participants or affect the benefit-risk profile?
- Do the changes impact the clinical study protocol or informed consent form?
- Do the changes impact the assessment of the expectedness of serious adverse events?
Often, the high-level SOC is prepared (along with updating the IB). The functional area leads will determine if the changes in their sections are “substantial” and should provide a detailed rationale for the changes.
5. Agree on SOC Format
There are two formats for a detailed SOC: a table format and a text format. Each has its strengths, and the choice often depends on the complexity of the changes, the preferences of the team, and specific requirements from regulatory agencies. The team should agree on the format early in the writing process.
The table format is widely used because of its ability to present information in a structured and visually accessible way. Substantial changes are organized into three columns: one for the original text, one for the new or updated text, and one for the rationale behind the change. This format works particularly well when the number of changes is moderate, as it allows reviewers to quickly compare updates side by side.
The text format, on the other hand, is better suited for cases involving numerous changes or updates to in-text tables. In this format, each substantial change is described in a narrative style, with the original text, updated text, and rationale presented as separate paragraphs. While less compact than the table format, the text format provides more flexibility when dealing with complex revisions or extensive content changes.
What if the IB goes through a complete overhaul in structure (perhaps using a new template)?
It is best if the structural changes to the IB are made first – to establish a new baseline before content changes are made. Regulatory agencies are most concerned with content changes, not structural changes. A tracked comparison with both structural and content changes can be very messy and hard to follow. With a new baseline established, a tracked comparison of the content changes will be clearer and easier to describe in an SOC (high-level or detailed).
How Often Should the Investigator’s Brochure Be Updated?
To maintain regulatory compliance, an Investigator’s Brochure must be reviewed annually to determine if updates are needed. IB updates provide investigators and ethics committees with accurate, up-to-date information. However, some circumstances—such as significant new safety findings—may warrant an update sooner than the one-year mark. Regular communication among regulatory, clinical, and medical writing teams helps determine the appropriate timing for these updates.
As Alexander Graham Bell once said: “Before anything else, preparation is the key to success.”Applying this principle to IB updates means taking proactive steps, like following the five tips outlined in this article, to simplify and streamline the process.
In a perfect world, adhering to these best practices would guarantee a smooth and efficient authoring process for the detailed SOC. The complexities of clinical research often demand additional expertise and collaboration. With extensive experience supporting IB updates and SOC development, Certara is ready to assist at every stage.
This blog was originally published on 2021 年 9 月 24 日, and was updated on 2025 年 2 月 19 日.
