Preparing the Investigator’s Brochure for Submission Under the EU Clinical Trial Regulation

According to EU Clinical Trial Regulation (CTR) 536/2014, the purpose of the Investigator’s Brochure (IB) is to provide the investigators and others involved in the clinical trial with information to facilitate their understanding of the rationale for, and their compliance with, key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures.

The form the Investigator’s Brochure (IB) takes depends on the current stage of development of the investigational medicinal product (IMP); in early-phase drug development, the Investigator’s Brochure (IB) will contain more non-clinical data, compared with an IMP in late-phase development, where the clinical data in the IB will be more extensive. Under the Clinical Trial Regulation (CTR), the Summary of Product Characteristics (SmPC) may serve as the IB after IMP authorisation in any EU country.

If the IMP is not yet authorised in the EU, the Investigator’s Brochure (IB) will be a separate document from the SmPC. In the case of trials conducted in more than one EU member state, the Investigator’s Brochure (IB) must be harmonised across all member states. For trial transitioning over from the Clinical Trial Directive (CTD), the Sponsor must provide a signed declaration that the Investigator’s Brochure (IB) is harmonised.

As with the Clinical Trial Directive (CTD), the Investigator’s Brochure (IB) should be reviewed at least once a year, preferably in parallel with the Annual Safety Report (ASR)/Development Update Safety Report (DSUR).

Reference Safety Information

The biggest change to the Investigator’s Brochure (IB) under the Clinical Trial Regulation (CTR) is the requirement of a reference safety information (RSI) section relating to product information about the investigational medicinal product (IMP), namely the expectedness of a given suspected serious adverse reaction (SAR). Expectedness should be determined by reviewing events observed with the investigational medicinal product (IMP) and not based on anticipated pharmacological properties of the class of drug.

What should be included in the reference safety information (RSI)?

The reference safety information (RSI) should contain a table of expected SARs that should be referred to by their MedDRA preferred term only. An expected serious adverse reaction (SAR) is one that has been observed more than once with reasonable evidence of a causal relationship between the event and the investigational medicinal product (IMP), after thorough assessment by the sponsor.

If the IMP is used for more than one indication, more than one reference safety information (RSI) section may be needed if the expected SARs differ depending on the indication. Likewise, separate RSI sections may be needed for different patient populations (i.e., adults, children).

In trials where a combination of IMPs was used, the Sponsor can either have one reference safety information (RSI) for each drug or create a combined table of expected SARs.

Any update to the reference safety information (RSI) would be a substantial modification under the Clinical Trial Regulation (CTR).

What should not be included in the reference safety information (RSI)?

• All SARs that are not considered expected by the Sponsor
• Any SARs that occurred only once, unless there is strong evidence of a causal relationship and robust justification based on medical judgement
• Serious events that are considered efficacy endpoints
• An overview of the overall safety profile of the investigational medicinal product (IMP) (this should be detailed in other sections of the Investigators Brochure and ASR)

How DLRC can help you with Investigator’s Brochures (IB)

DLRC Medical Writers and Regulatory Professionals can advise you on EU CTR requirements and assist in transitioning your documents from Clinical Trial Directive (CTD) to Clinical Trial Regulation (CTR). DLRC Medical Writers have a wealth of experience writing IBs and will be able to assist with writing/updating the Investigator’s Brochure (IB) and review the reference safety information (RSI) to make sure it is CTR-compliant.

To find out how DLRC’s experts can help you, email us at hello@dlrcgroup.com or use the links below.