As a medical writer at Synchrogenix, a Certara company, I work with many different pharmaceutical companies on many different regulatory documents. One of these documents is the Investigator’s Brochure (IB), a complex document that summarizes the clinical and nonclinical data on an investigational drug product. IBs are living documents, and, at minimum, are updated annually. Being the medical writing lead on an IB update can be challenging, as it requires input from and collaboration between team members from many different functional areas, ranging from Chemistry, Manufacturing and Controls (CMC) to nonclinical and clinical pharmacology and pharmacovigilance. Project management skills come in handy when authoring an IB update!
But what people forget to tell you is that an IB update is not always “just” an IB update. Depending on the situation, you may need to provide a detailed overview of the changes made to the IB. This detailed overview is called a “summary of change document” or simply SOC and presents before and after text using strikethrough and bold font to show the changes made. The detailed SOC is not to be confused with the summary of changes often found at the beginning of an IB, which presents a high-level overview of the changes made. The process of generating a detailed SOC differs from company to company. Because the detailed SOC uses the final, approved IB language, authoring of the detailed SOC often seems an afterthought and is crammed into the few days left before the IB needs to be distributed to regulatory agencies (and Ethics Committees and/or Independent Review Boards as applicable) and investigators at participating clinical sites. Here are 5 tips to streamline developing a detailed SOC that will help relieve some of the last-minute stress:
1. During the kickoff meeting, ask your regulatory affairs representative whether a detailed SOC is required.
Frequently, a high-level overview of changes and the rationale for these changes is sufficient. However, sometimes, a more detailed depiction of changes may be required. One of these situations is when one of your clinical trials is conducted in France. The French National Agency for the Safety of Medicines and Health Products (ANSM) may want to see more detail. Your regulatory affairs representative will know whether a detailed SOC is required based on their interactions with health authorities worldwide. Identify this need early!
2. Generate a high-level summary of changes while you are updating the IB.
Don’t wait until all the changes have been made in the IB to generate a high-level overview of changes. For a high-level overview of changes, it is sufficient to state that results from a new nonclinical study were added, pharmacokinetics data were updated, or event X was added to the list of adverse drug reactions (ADRs). The text in the relevant sections in the IB does not need to be final at this time. The high-level overview of changes is an excellent source for the detailed SOC (see tip 4).
3. Get team alignment on the rationale for each change.
Medical writers are often tasked with providing the rationale for the changes. For many changes, the rationale may be as simple as “new data were available.”For other changes, the rationale may not be that simple: why was the list of ADRs updated to include event X? Make sure that the team has sufficient time to provide you with and confirm the rationales for the changes in the high-level overview of changes. You will use the same rationale for the changes included in the detailed SOC.
4. Get team alignment on what is considered a substantial change.
The need for a detailed SOC stems from the requirement to notify certain health authorities of substantial amendments to clinical trials. The French Agency for the Safety of Health Products (Afssaps) released a practical guidance document to help determine substantiality of clinical trial changes in 2009 . When assessing substantiality of changes made in the IB, the team needs to consider the following:
- Do the changes affect the safety of the clinical study participants?
- Do the changes impact the clinical study protocol?
- Do the changes impact the assessment of the expectedness of a suspected serious adverse effect?
If the answer to any of these questions is “yes,” include the change in the detailed SOC. Please note that it is not the medical writer’s responsibility to establish substantiality. Rather, it is the sponsor’s responsibility. The team should notify the medical writer which changes are deemed substantial and to be included in the detailed SOC.
5. Agree on the format of the detailed SOC ahead of time.
There are 2 formats for the detailed SOC: a table format and a text format. The table format appears to be the most frequently used format, although both formats are accepted. In the table format, the substantial changes are presented using 3 columns: 1 column for original text, 1 column for the new or updated text, and 1 column for the rationale of the change. If the substantial changes are numerous or contain many updates to in-text tables, use the text format. In the text format, the content of the columns is presented as separate paragraphs. In my experience, clients have their preferences, and it is therefore wise to get agreement on the format ahead of time.
As Alexander Graham Bell once said: “Before anything else, preparation is the key to success.”In a perfect world, following these 5 tips would guarantee a smooth and successful authoring process for the detailed SOC accompanying your IB update. In the real world, it may require more than this. We have many years of experience authoring IB updates and detailed SOCs. If you need additional help, feel free to reach out!
 Agence nationale de sécurité du médicament et des produits de santé. http://www.afssaps.fr/var/afs…5d129a748e6ad03f3c8c48df8.pdf (europa.eu)