HARMONIZING INVESTIGATIONAL AND POST-MARKETING SAFETY REPORTING

The safety of patients receiving drug or biologic products is paramount in both the investigational and post-marketing settings. Preparing routine required safety updates can be an arduous and time-consuming process with different data lock points (DLPs), Reference Safety Information (RSI), and reporting timeframes for clinical studies and post-marketing reports. This month, I thought I would take a step back and talk about periodic safety reporting in both the investigational and post-marketing setting and how one can streamline the process. This blog will focus on routine required reports, not expedited reporting.

Starting with the investigational phase, there is a requirement to provide safety updates to both US INDs and CTAs in the EU and other regions. An important point to consider is a single US IND covers a development program consisting of a number of studies supporting an indication while a CTA is for a specific study. Thus, one IND may contain multiple studies ranging from Phase 1 first in humans (FIH) to post marketing studies while each CTA is for an individual study only. In either case, the same product may span multiple INDs or CTAs.

ICH E2F provides for the Development Safety Update Report (DSUR), a format for providing updates on safety information for a product across multiple clinical trials which is accepted in all ICH regions. With this guidance, one DSUR can be prepared for multiple studies globally and submitted in the US in lieu of an IND annual report (Note: information required by 21CFR Part 312 is included as an appendix to the DSUR).

Generally, a single DSUR is prepared for each active ingredient and the Development International Birth Date (DIBD), which is the sponsor’s first authorization to conduct a clinical trial in any country worldwide, is used as the start of the annual period for the DSUR.

Once a product is approved, there is again a need for post-marketing safety reporting. In the US, this is covered under 21 CFR Part 314.80 for drugs (PADER) and 21 CFR Part 800.80 for biologics (PAER). Reports are required quarterly for the first three years and yearly thereafter. In other regions, this requirement may vary (e.g., annual reporting initially and less frequently for products that have been on the market for a period of time).

In 2011, the ICH endorsed the ICH E2C Periodic Safety Update Report (PSUR) Guideline (ICH E2C(R1) guideline), which established the PSUR as a harmonized format for post-marketing periodic safety reports for approved drug and biologic products, and described the format, content, and timing of PSUR submissions.

FDA has routinely accepted the PSUR in lieu of a PAER/PADER with the caveat that quarterly reports be submitted for the quarters in which the PSUR is not submitted for the first 3 years. For sponsors who have a product approved in the US and another region such as the EU, the PSUR became the most appropriate method for harmonized post-marketing safety reporting.

In 2016, this guidance was updated (ICHE2C(R2)) to the Periodic Benefit-Risk Evaluation Report (PBRER). The PBRER is intended to be a common standard for periodic benefit-risk evaluation reporting on marketed products (including approved drugs that are under further study) among the ICH regions and replaces the PSUR.

The PBRER is meant to contain a comprehensive review of the safety information on all uses of the product including information generated in clinical studies, post-marketing and off label use setting.

Due to its comprehensive nature, information included in the PBRER can also be used to populate sections of the DSUR, and the guidance provides a table mapping these sections.

There are also guidances which provide information on how a sponsor can harmonize the DLP for the PBRER and DSUR since the DSUR timeframe is generally based on the DIBD while the PBRER uses the first marketing application approval date. In synchronizing the DLPs for the DSUR and PBRER, the period covered by the next DSUR should be no longer than one year. Approval from the relevant regulatory authorities to synchronize the DLPs is required, and in the US, this is commonly done with a waiver request.

Multiple sources of reference safety information (RSI) may apply to a single product as the RSI section of the Investigator’s Brochure (IB) is used in the investigational phase and the approved labeling is used in the marketing setting. Sponsors may choose to develop a Company Core Data Sheet (CCDS) which includes an overview of the product including safety and indications with the Company Core Safety Information (CCSI) within the CCDS serving as the RSI.

While requiring greater planning and coordination on the part of the sponsor, it is possible to generate one document, the PBRER, which provides comprehensive safety information about the product. This document can be used as the basis for both IND/CTA annual safety reporting in addition to post‑marketing safety reporting as the relevant PBRER sections can be used to populate the DSUR. Below is a listing of the items in each of these reports with the common information mapped together.

* Information in these sections may be different in the PBRER and DSUR.