Drugs are approved for marketing on the basis of clinical trials that are, generally speaking, carried out on relatively small numbers of people. The goal of these trials are to identify the risks inherent in taking a drug while also assessing the drug’s efficacy in the treatment of the intended indication. However, once a drug has reached the market, far more individual patients may be exposed to the drug than were exposed during clinical trials. Regulatory agencies recognize that much larger populations being administered a drug has the potential of uncovering rarer side effects that were not seen during clinical testing. As a result, drug manufacturers are required to provide regulatory agencies with periodic updates of safety.
One such safety update is the Periodic Safety Update Report or PSUR. PSURs are provided every six months, at minimum, to the FDA, the European Medicines Agency (EMA), and to other regulatory agencies in regions in which a drug is marketed. The focus of the PSUR has primarily been to provide an analysis of safety signals, including line listings of adverse events (AEs) and serious adverse events (SAEs) to regulatory agencies. Special focus is paid to serious adverse drug reactions and any changes to known drug reactions (e.g., severity, frequency, target population). While changes in efficacy are reported, they are not the primary focus of this document.
The format of PSURs, however, has begun to change.
The International Congress on Harmonization (ICH) released a draft guideline “Periodic Benefit-Risk Evaluation Report (PBRER) E2C (R2)” approved through Step 2 of ICH approval processes on 01 February 2012. The ICH guideline outlines the format, content, and timing of a PBRER for an approved drug or biologic. Following suit, both EMA and FDA released corresponding draft guidances. On 15 November 2012, the ICH guideline was approved by the ICH Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies of the European Union (EMA), Japan (MLHW) and the USA (FDA). The new format came into effect for the EMA in July of 2012. We’ve not yet seen formal notification of adoption by the FDA yet; however, upon release of the draft guidance, it was suggested that once the guideline was finalized, applicants could submit a waiver request for submission of the PBRER in the United States in place of a periodic adverse drug experience report for a new drug application, for an abbreviated new drug application, or for a biologics license application.
The new format for PSURs is called the Periodic Benefit-Risk Evaluation Report and departs rather significantly from the older PSUR format still currently in place in the US. The structure of the reports , as provided in guidances, are significantly different. More important than structure, however, the general focus of these documents is significantly different. In the PBRER, gone are the extensive line listings of AEs and SAEs. Because of new EMA guidelines for AE and SAE reporting, the agency should be receiving these listings more frequently than the 6 month time frame of a PSUR.
As the name implies, the PBRER is not focused primarily on signals of safety, but on an integrated risk‑benefit analysis. As such, in addition to presenting identified safety risks, the PBRER format also includes an analysis of the benefit the drug provides. Therefore, in addition to safety signals, the PBRER demands an analysis of efficacy and effectiveness (note: efficacy and effectiveness are not harmonized terms and mean different things in different regions). This benefit analysis includes previously known effectiveness data as well as new information on drug efficacy and effectiveness. Therefore, the PBRER has a much more integrated view of a drug’s usefulness in the patient population.
Functionally, the adoption of the PBRER by EMA and not by FDA or various other agencies worldwide has led to a bit of a headache for companies that market their drugs in multiple regions. Two PSURs have to be drawn up, rather than a single harmonized report that works across the globe. While some of the required information contained in the two formats overlaps, a good deal if it is different. As previously stated, however, FDA is expected to begin accepting the PBRER format of the PSUR in the near future, alleviating this issue for drugs marketed in both the US and Europe.