Investigator’s Brochure (IB) Guide: A Full Workflow Analysis
from FDA/ICH Regulations & RSI Authoring
to eCTD Submission & Annual Updates

When developing an Investigator’s Brochure (IB) template, sponsors and medical writers must primarily consult the ICH guidelines. The ICH E6(R3) guideline, in particular, defines the mandatory content structure—for instance, Appendix A outlines the required sections, such as the title page [1]—and establishes the baseline for sponsors by mandating the minimum information an IB must contain [2].
However, adhering to this content checklist alone is not sufficient. The preceding guideline, ICH E6(R2), also provides recommendations on formatting—specifically the use of tables—intended to improve clarity. These formatting suggestions, however, can introduce significant challenges for localization and desktop publishing (DTP) [3].
This emphasis on specific formats like tables, combined with the highly technical nature of the IB document, creates a significant challenge for translation and layout in non-English speaking countries. Therefore, a critical consideration when designing an IB template is how to ensure the accuracy of the specialized content from the very beginning. For example, when selecting translation partners, it is vital to verify that their teams possess the relevant medical and regulatory background to ensure that all technical terminology remains precise post-translation.

For clinical trials conducted in the US, the Investigator’s Brochure (IB) must meet core FDA requirements. This is not just a best practice; it is a legally binding obligation that Regulatory Affairs (RA) departments must strictly adhere to when preparing submission dossiers.The fundamental legal requirement stems from 21 CFR 312.55. This regulation explicitly states the sponsor’s obligation to “shall give” the IB to investigators before the study begins. Official FDA documentation states:

“The regulations pertaining to providing investigators with an investigator brochure are found in 21 CFR 312.55… Sec. 312.55 Informing investigators. Before the investigation begins, a sponsor… shall give [Emphasis added.] each participating clinical investigator an investigator brochure… ” [4]

Second, the IB is a critical component of the IND (Investigational New Drug) package. According to 21 CFR 312.23(a)(5), an IB must be included in the IND if the sponsor is not a sponsor-investigator.

“An IB must be included in the IND if the sponsor is not a sponsor-investigator.26… 26 See 21 CFR 312.23(a)(5); 21 CFR 312.55. ” [5]

The review chain for the IB does not end with the sponsor and investigator. The FDA further confirms that the IRB (Institutional Review Board) must also review the IB to protect subject welfare.

“The purpose of IRB review is to assure… that appropriate steps are taken to protect the rights and welfare of humans… IRBs use a group process to review… (e.g., informed consent documents and investigator brochures)…7” [6]

These three regulatory pillars form the cornerstone of compliance. For RA departments, the pain point is clear: when preparing an IND submission dossier (e.g., translating from Chinese to English for an FDA submission), the accuracy and compliance of the IB translation are paramount. Therefore, when preparing files aligned with investigator’s brochure fda guidance, a suggested consideration is to ensure any translation partners not only understand the language but also the gravity of these FDA regulations, and possess experience handling compliant submission dossiers like an IND submission dossier.

The Investigator’s Brochure (IB) plays a central role in Good Clinical Practice (GCP), and its importance is clearly defined in the ICH E6 guidelines. A key requirement of GCP is ensuring the investigator is fully informed about the investigational product.ICH E6 section 4.1.2 mandates that the investigator has an obligation to be “thoroughly familiar with” the IB’s contents. As the ICH E6(R2) guideline states:

“4.1.2 The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator’s Brochure… ” [7]

This is a critical GCP obligation. If an IB (e.g., in a multinational trial) is not translated into a language the investigator can understand, they objectively cannot fulfill this GCP duty. This directly impacts trial quality and subject safety.

Furthermore, ICH E6 7.1 (FDA version) defines the GCP purpose of the IB: to enable a clinician “to understand it” and make an “unbiased risk-benefit assessment.”

“…enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. ” [2]

For clinical and medical writing departments, this creates a core pain point: the GCP documents they handle (like the IB, Protocol, ICF) are “very professional.” If the translation quality cannot be guaranteed, GCP compliance is directly jeopardized. Therefore, a critical consideration during localization is the implementation of a rigorous quality control process, such as adopting the international standard TEP (Translating, Editing, and Proofreading) process and ensuring that translators possess the relevant professional background.

For medical device sponsors, IB authoring and localization have specific regulatory requirements, especially in the EU. The EU’s Medical Device Coordination Group (MDCG) released MDCG 2024-5 in 2024, which is the definitive guidance on the content of medical device IBs.[9] A critical requirement of this guidance is that the IB’s description must be “as clear and fundamental as reasonably possibly,” not assuming the reader is an expert. This places a high demand on localization for “scientific transcreation.” The MDCG guidance states:

“The guidance states that “the description should be as clear and fundamental as reasonably possibly, not assuming that all intended readers are already experts in the field.” ” [10]

This requirement directly hits on the pain point faced by medical device regulatory affairs clients under MDR/IVDR. EU regulations mandate that key documents like Labelling and IFU must be translated into all 24 official EU languages, all while maintaining the “clarity and fundamentality” demanded by MDCG.

Therefore, when considering a localization strategy, medical device sponsors must prioritize a vendor’s ability to handle the specific regulations of the medical device field. An important consideration is whether the vendor holds certifications like ISO 13485:2016 (Medical Industry) and has experience managing all 24 official EU languages.

The Investigator’s Brochure (IB) is not a static document. Sponsors have an obligation to continually review and update it, especially when new safety information emerges. The ICH E6 guideline recommends the IB be reviewed at least annually, and revised more frequently if needed.

“The investigator brochure must be reviewed at least annually… The ICH E6 guideline suggests reviewing it at least once a year. But, updates can happen more often based on the trial’s progress. ” [11]

FDA regulations are even more continuous; 21 CFR 312.55 requires the sponsor to keep investigators informed “as the overall investigation proceeds,” for example, through “periodically revised investigator brochures.”

“The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of new observations… Such information may be distributed to investigators by means of periodically revised investigator brochures… ” [12]

The crux of this update process is that when a sponsor issues a revised brochure (e.g., due to new safety information), real-world IRB policies (like JHU’s) require the investigator to “submit the revised brochures to the IRB.”

“…the sponsor will issue a new brochure to investigators. Sponsors expect investigators to submit the revised brochures to the IRB as they are issued. ” [13]

This creates immense time pressure for localization. The core pain point for Pharmacovigilance (PV) departments, especially when handling urgent updates triggered by SUSARs, is the need for “Quick TAT” (Quick Turnaround Time), often with a “maximum of 3 days” to complete translation and submission. Therefore, an effective operational model must support this urgent delivery. A suggested consideration is to assess whether a partner has experience handling “rushed deadlines,” for instance, by possessing the flexibility to divide work among multiple linguists and production teams to meet the demand.

The core of the Investigator’s Brochure (IB) is its scientific content. ICH E6(R3) confirms the IB is “a compilation of the clinical and nonclinical data on the investigational product(s).”

“The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s)1 that are relevant to the study of the product(s) in human participants. ” [14]

This core content, such as “preclinical studies” (including “toxicology”) and “clinical studies,” is “very professional.” This leads to a core pain point for medical writing managers and non-clinical experts: how to guarantee the quality and accuracy of this specialized content during cross-language processes (like translation).

Furthermore, specific regions (like China’s NMPA/CDE) have unique requirements for IB content for certain drugs. For example, IBs for Traditional Chinese Medicines (TCMs) must include China-specific content, such as “formulation theory basis.”

Given this high level of specialization and regional specificity, a key consideration when preparing investigator’s brochure medical writing or its translation is to ensure professional matching. A recommended approach is to establish a mechanism ensuring that documents for different fields (e.g., toxicology, pharmacology, clinical medicine) are handled by experts or translators with the corresponding professional background, to maintain content integrity.

Investigator’s brochures translation is not just a linguistic task; it is a GCP-regulated compliance activity. The legal notice of ICH E6(R3) explicitly recognizes “translation” as a “modification” of the document and requires “reasonable steps” for labeling, making the translation process an auditable part of GCP.

“Legal notice:…may… be used, reproduced… translated… In case of any… translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify ” [15]

A failure in translation quality is a failure in compliance. FDA Warning Letters provide legal precedents where “Incorrect translation” [16] or failure to “provide an English translation” [17] led to non-compliance. In China, the CDE (NMPA) also clearly states that import manufacturers are “responsible for errors caused by language translation” [18]. This magnifies the pain point for procurement and localization managers: on one hand, they worry about non-compliant translation quality; on the other, they face pressure to control costs and worry that “prices are too high.”

When balancing compliance and cost, a key strategic consideration is leveraging technology for long-term cost control. The suggested approach is to utilize Translation Memory (TM) technology. By establishing and maintaining a TM early, companies can ensure “the same sentence never needs to be translated, or paid for twice.” For example, adopting the international standard of pricing by source word count and offering discounts (e.g., 30%-70%) for repetitions matching the TM is an effective way to achieve long-term cost control and ensure consistency.

The Investigator’s Brochure (IB) is not an isolated document. It is an integral part of the complete Clinical Trial Application (CTA) and regulatory dossier, tightly linked to the IND, IMPD, Protocol, and CTD.In the EU, the IB’s relationship with the IMPD (Investigational Medicinal Product Dossier) is particularly close. EMA guidance requires that in the CTIS transition, the IB and IMPD must be “consolidated/harmonised.”

Part I. ✓Protocol (consolidated/harmonised). ✓Investigator’s Brochure (consolidated/harmonised) or SmPC for marketed product. ✓IMPD (consolidated/harmonised). [19]

EU guidance even explicitly allows the “Safety and Efficacy” section of the IMPD to “reference… the Investigator’s Brochure” [20], and industry interpretation confirms “Referring to the IB… the IMPD can be prepared” [21]. This dramatically magnifies the risk of an IB translation error, as one mistake could be referenced across multiple submission documents.

In the US, the IB is part of the eCTD (Electronic Common Technical Document) submission. FDA guidance confirms the IB is part of the CTD-formatted electronic submission, advising:

“…guidance on electronic IND submissions in the Common Technical Document (CTD) format… You should provide the investigator’s brochure as a single PDF file. ” [22]

This creates a significant pain point for Regulatory Affairs (RA): they must translate and manage an entire suite of complex, interrelated dossier documents, ensuring 100% terminological consistency between files like the IB and IMPD. Therefore, a critical consideration when selecting partners is their understanding of the entire ICH CTD structure (M1-M5) and regional electronic document structures (like eCTD) to ensure this cross-file consistency.

Among all sections of the Investigator’s Brochure (IB), the Reference Safety Information (RSI) is perhaps the most regulatorily impactful. The RSI is the sole basis for judging the “expectedness” of SUSARs (Suspected Unexpected Serious Adverse Reactions). ICH E6(R3) clearly defines the RSI as “contained in the IB” and serving as an “important reference point for expedited reporting of… SUSARs.”

“The reference safety information (RSI) contained in the IB provides an important reference point for expedited reporting of suspected unexpected serious adverse reactions (SUSARs)… This list should be used for determining the expectedness… ” [23]

FDA guidance (E6(R3)) confirms this, stating the RSI is contained in the IB and used for determining “expectedness” [24]. However, the definition and application of the RSI are complex in practice. FDA official Q&A acknowledges “quite a bit of confusion” surrounding the RSI and that the industry is seeking “consistency” [25].

This complexity makes the translation of specialized safety sections—like RSI, toxicology, and pharmacology—a high-risk area. The core pain point for Pharmacovigilance (PV) and toxicology experts is “how to ensure the professional accuracy” of this key safety information during translation. A single mistranslated word (e.g., translating “possible” as “rare”) could completely alter an adverse event’s expectedness, leading to severe compliance consequences.

Therefore, when handling the investigator’s brochure rsi and toxicology sections, a necessary consideration is to employ professional matching. It is essential to ensure that the personnel translating these critical sections have the corresponding professional background (e.g., “pharmacology” or PV) to guarantee the RSI retains 100% of its original legal and scientific meaning across languages.

The Investigator’s Brochure (IB) for a medical device has specific regulatory requirements distinct from pharmaceuticals. In the EU, the MDR (Medical Device Regulation) mandates that clinical investigation applications for medical devices must include an IB. MDR Annex XV (Clinical Investigations) explicitly states:

“For investigational devices covered by Article 62, the sponsor shall… submit the application… accompanied by the following documents:… Investigator’s Brochure. 26” [26]

The requirements for a device IB are jointly defined by the MDR and ISO 14155:2020 (device GCP). The core purpose of the MDCG 2024-5 guidance is to harmonize these two, helping sponsors develop an IB that complies with both EU MDR and ISO 14155:2020.

“…MDCG 2024-5 is aimed at helping sponsors develop their IB in accordance with both EU MDR and ISO 14155:2020… 27” [27]

The pain point for medical device Regulatory Affairs (RA) is the need to handle device-specific regulatory document types. For example, the MDR requires that the IFU (Instructions for Use) and Labelling be translated into the official language(s) of the member state (up to 24 languages in the EU).

Therefore, when selecting a localization partner, device sponsors must consider their specific qualifications in the medical device sector. A critical consideration is whether the vendor holds the “ISO 13485:2016 (Medical Industry)” certification, the gold standard for quality management in the device industry, and confirm they have practical experience handling “IFU,” “Labelling,” and the “Clinical Trial Application Dossier.”

IB translation and localization must meet the regional compliance requirements of different regulatory agencies. A core pain point for Regulatory Affairs (RA) is managing the divergent requirements of global agencies like the FDA, EMA, Health Canada, and NMPA. For example, in Canada, Health Canada strictly ties the definition of an “unexpected” adverse reaction to “the risk information set out in the investigator’s brochure.”

“A serious adverse drug reaction that is not identified in… the risk information set out in the investigator’s brochure… ” [28]

In a bilingual country like Canada (English/French), this requirement means that the RSI (Reference Safety Information) in both language versions must be 100% legally and scientifically equivalent. Any discrepancy in translation could lead to critical errors in judging the “unexpectedness” of an adverse reaction.

Compliance requirements vary widely by region. For instance, while Japan and Korea might accept Modules 3-5 in English, the EU has strict 24-language mandates for medical device IFUs and Labelling.

Therefore, for sponsors conducting global trials, a key strategic consideration is to establish a translation compliance framework that can meet the requirements of different global agencies (US, Europe, Japan, China, etc.). This necessitates partners who not only translate language but also understand and execute the specific compliance nuances of agencies like the FDA and EMA.

The Investigator’s Brochure (IB) is an indispensable standard document in real-world clinical trial operations. By analyzing public protocols on ClinicalTrials.gov, we can see the practical application of IBs in trials for specific products like Aducanumab and BIA 10-2474.For instance, in the protocol for an Aducanumab (aducanumab-avwa) trial (NCT05108922), the “Investigator Brochure” is explicitly mentioned.

“The protocol mentions the Investigator Brochure (IB)… The only mention of Aducanumab in this section… is in the context of an amendment… to align with a recent label update to aducanumab-avwa. ” [29]

Similarly, in another trial (NCT03386487), the protocol references the “Investigator’s Brochure for PF-04457845” (an FAAH inhibitor often discussed in relation to BIA 10-2474).

“…and can also be found in the Investigator’s Brochure for PF-04457845. ” [30]

These real-world examples from ClinicalTrials.gov confirm that the IB is the core legal and scientific document used by sponsors and clinical operations teams to convey critical product information (including updates) to investigators.

The fundamental purpose of the Investigator’s Brochure (IB) is clearly defined in ICH E6 7.1 (FDA version). It is not merely a data dump; it exists to “support the clinical management of the study subjects.” According to ICH (via FDA) guidance, the purpose of the IB is to provide investigators and clinicians with information to:

“Its purpose is to provide the investigators… with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol… The IB also provides insight to support the clinical management of the study subjects… ” [31]

The IB is the key reference for clinicians and investigators managing subjects during a trial. However, when preparing an IB for a global trial, the core pain point for clients (like medical writers and clinicians) is: “How do you ensure accuracy and… consistency across multiple languages?”

If subtle discrepancies exist between different language versions of the IB, the investigator’s understanding of the protocol rationale or their clinical management of subjects could deviate, jeopardizing trial integrity.

Therefore, during the preparation phase of the IB, a critical consideration is to establish technical controls before translation begins. For example, priority should be given to creating a “glossary” to lock key terms and maintaining a “‘clean’ and ‘consistent’ TM” (Translation Memory) to technically ensure the accuracy and uniformity of all information.

The Investigator’s Brochure (IB) is not only a scientific document but also a sensitive legal and administrative one. ICH E6(R2) explicitly includes a “Confidentiality Statement” within the required content structure of an IB.According to the ICH E6(R2) guideline, the IB should include:

“The IB should include the following sections… Confidentiality Statement ” [32]

As a “confidential document,” the IB contains a sponsor’s most critical intellectual property (e.g., in early development, it might contain core assets like protein sequences). This creates a core administrative pain point for legal, procurement, and regulatory affairs departments: “information security.” They must ensure this confidential information is not leaked during processes like translation or outsourcing.

Therefore, strict information security management must be considered during the IB’s administration and transfer. A suggested consideration is to evaluate a partner’s security credentials, such as whether they hold “ISO 27001 information security certification.” Furthermore, it’s crucial to technically ensure “encrypted file transmission” and utilize an “online project management system” to strictly control project permissions and file transfers/downloads, thereby mitigating the risk of leaks procedurally.

As product development progresses, sponsors often need to manage multiple versions of an IB for a single product used in different trials. The existence of “multiple versions” is confirmed by real-world trial protocols on ClinicalTrials.gov (NCT03107988). This protocol references an:

“Investigator’s Brochure (v 10/2018) of… functioning and includes multiple versions. ” [33]

When one product is used in different trials, or when the IB is frequently updated with new data, Clinical Operations Directors and Localization Managers face a severe pain point: ensuring “consistency,” especially “when more than one translator is working on the same project.”

If Version A of the IB translates an adverse event as “headache,” but Version B (or a different translator on the same project) translates it as “head discomfort,” it creates data and compliance chaos.

Therefore, the advanced challenge of managing a multiple version investigator’s brochure requires technology-driven consistency management. A key consideration is the use of terminology and translation memory (TM) technology to maintain consistency. A suggested solution is the adoption of “a centralized translation memory (TM) database,” ensuring all versions and all team members share the most up-to-date, unified corpus, technically guaranteeing consistency.

The Investigator’s Brochure (IB) is equally applicable to clinical research for specific substances like psychedelics. In these high-profile fields, the IB is the key document ensuring investigators fully understand the risks and procedures.For example, the protocol for an MDMA trial (NCT01458327) sponsored by MAPS (Multidisciplinary Association for Psychedelic Studies) explicitly stresses the IB’s importance, requiring it to be read.

“A comprehensive review of MDMA research is included in the Investigator’s Brochure supplied by the Sponsor. This document should be reviewed prior to initiating the protocol. ” [34]

Likewise, in trials involving Psilocybin, the IB is a standard document. A trial (NCT06368492) where Psilocybin is supplied by the Usona Institute directs investigators to the IB for details.

“Detailed information about psilocybin… can be found in… the Psilocybin Investigators Brochure… The psilocybin capsules… will be supplied by the USONA Institute… ” [35]

Another trial (NCT05128162) also references the IB provided by Usona Institute (coded Tryp-8802).

“Psilocybin. Manufacturer. Usona Institute…. Dosing regimens have ranged from… (Tryp-8802. Investigator’s Brochure). ” [36]

These examples show that whether for MAPS or Usona, when researching specific substances like MDMA or Psilocybin, the IB is the standard, regulatory tool used by sponsors to convey comprehensive research information to investigators and ethics committees.

The Investigator’s Brochure (IB) plays a critical “referee” role in the Adverse Event Reporting process. Specifically, the RSI (Reference Safety Information) list within the IB is the basis for determining if a Serious Adverse Event (SAE) requires “immediate reporting.”Health Canada’s guidance explicitly states that the IB can be used to identify those SAEs that do “not needing immediate reporting”—precisely because they are already listed as known risks.

“…all SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting. ” [37]

The IB (especially its RSI list) is strongly linked to adverse event reports (like SUSARs). This highlights a recurrent pain point for Pharmacovigilance (PV) departments: IB updates (especially safety listings) are extremely time-sensitive. When a new, serious, unexpected adverse reaction (i.e., a SUSAR) occurs, the PV department must rapidly update the RSI and distribute the updated IB. This process often requires “Quick TAT” (Quick Turnaround Time), frequently “3 days maximum.”

Therefore, when managing IB updates, especially those involving the investigator’s brochure adverse event listing, it is essential to have an operational process that can respond to “rush jobs.” A key consideration is whether a partner has the flexibility and resources to meet these “quick turnaround” demands.

The Investigator’s Brochure (IB) must not only be compliant in content but also in its technical submission format, especially within an eCTD (Electronic Common Technical Document) submission.ICH M4 (CTD) confirms the integrated relationship between GCP (which covers the IB) and the CTD. The IB is part of the CTD-formatted submission [1].In its guidance on eCTD submissions, the FDA specifies the IB’s position and technical format, stating that sponsors “should provide the investigator’s brochure as a single PDF file.”

“…guidance on electronic IND submissions in the Common Technical Document (CTD) format… You should provide the investigator’s brochure as a single PDF file. ” [38]

For Regulatory Operations and eCTD submission managers, this technical aspect is a core pain point. When an IB (or other CTD document) requires translation, they worry that a translation vendor “cannot handle XML” formats, or that the translation workflow (e.g., exporting to Word and re-importing) will break the eCTD’s TAGS structure, causing the submission to fail at the regulatory gateway.

Therefore, when handling an IB destined for an eCTD submission, a critical technical consideration is ensuring the translation partner has the capability to process eCTD files. It is essential to confirm they “are 100% capable and experienced in handling such file formats (XML)” and can guarantee that “TAGS will be protected by tools and will not be deleted or changed” during the translation process, thus ensuring the structural integrity of the eCTD submission.