Reference Safety Information [RSI]

Document used for the assessment of the expectedness of all ‘suspected’ serious adverse reactions that occur in clinical trials. It is recommended to include this information either in a subsection on Safety under ‘Effects in Humans’ or in the section ‘Summary of Data and Guidance for the Investigator’, in accordance with ICH E6 (R2) guidance.

Reference Safety Information (RSI) is a critical component in the management of drug safety during both the pre-market (clinical development) and post-market phases. It serves as the standard against which new safety information is compared to identify potential safety issues or changes in the known risk profile of a product.

Reference Safety Information in the Premarket Setting (Clinical Development)

1. Definition: During clinical development, RSI typically consists of a summary of the known and potential risks of a drug, based on preclinical and clinical data available at that time.
2. Purpose: It is used to assess the relevance and seriousness of adverse events (AEs) that occur during clinical trials.
3. Location: In the premarket setting, RSI is usually found in the Investigator’s Brochure (IB) and the study protocol. The IB is a comprehensive document that includes the preclinical and clinical data on the investigational product up to that point.
4. Updates: RSI in the IB should be regularly updated as new safety data becomes available during the course of clinical development.

Reference Safety Information in the Post-Market Setting

1. Definition: In the post-market phase, RSI refers to the established safety profile of the drug as described in the approved product labeling.
2. Purpose: It serves as a benchmark for the ongoing evaluation of the drug’s safety profile in the post-marketing phase, particularly for the identification of new safety issues or changes in the frequency of known risks.
3. Location: The RSI is typically found in the Summary of Product Characteristics (SmPC) in Europe or the Prescribing Information (PI) in the United States. These documents contain detailed information about the drug’s indications, dosing, contraindications, and known risks.
4. Relevance: Health authorities, such as the FDA or EMA, require that adverse events reported post-marketing are compared against the RSI to determine if there are new risks or changes in the known risk profile of the product.

Comparison and Integration

• During Clinical Development: RSI is dynamic and evolves as more data is gathered. It is primarily used for the safety assessment of the investigational drug in clinical trials.
• In the Post-Market Phase: RSI is more stable but can be updated based on post-marketing surveillance data. It is used to identify new safety signals and to inform healthcare professionals and patients about the risks associated with the drug.

Importance

The management of RSI is crucial in both settings. In clinical development, it guides the safety monitoring and reporting processes. Post-marketing, it is essential for the continuous assessment of the benefit-risk balance of the drug. The accuracy and completeness of RSI directly impact the identification and management of potential safety issues, thus playing a vital role in ensuring patient safety.