Periodic Safety Report: DSUR, PSUR, PBRER, ASR, IB, Orphan Designation Annual Report

During the drug development and after the drug is on the market, the sponsor or market authorization holder has obligations to submit the safety information to regulatory agencies periodically. These periodic reports have different requirements and sometimes are confusing. While these reports may be prepared by the regulatory affairs department or pharmacovigilence department, biostatistics group may often be asked to provide the information for these periodic reports.

These reports and their abbreviations could be very confusing especially for those who are not working in the pharmacovigilence department: DSUR, IND Annual Report, ASR, IB, PSUR, and PBRER… If we take a close look at these reports, they may be considered as four types:

• DSUR (replacing IND Annual Report and Annual Safety Report) for drugs under developments
• PBRER (replacing PSUR) for drugs already on the market
• IB is required whenever there is a clinical trial
• Orphan Designation Annual Report is required for the developing product with orphan designation - for rare disease

DSUR:  Development Safety Update Report

According to ICH E2F “Development Safety Update Report”,

The Development Safety Update Report (DSUR) proposed in this guideline is intended to be a common standard for periodic reporting on drugs under development (including marketed drugs that are under further study) among the ICH regions. US and EU regulators consider that the DSUR, submitted annually, would meet national and regional requirements currently met by the US IND Annual Report and the EU Annual Safety Report, respectively, and can therefore take the place of these existing reports

ICH E2F Guideline is finalized in August 2010 and is replacing the previous IND (investigational new drug) Annual Report (in US) and Annual Safety Report (in EU). Other documents regarding DSUR can be found at ICH.org website

• Concept Paper
• Business Plan
• DSUR Examples Commercial Sponsors
• DSUR Examples non-Commercial Sponsors
• Presentation on E2F

IB: Investigator Brochure

According to ICH E6 “Good Clinical Practice”,

The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial.

For post marketing commitment clinical trials, the product label (package insert) may be used in place of the investigator brochure since the package insert includes the contents required in the investigator brochure.

Orphan Drug Designation Annual Report 

21CFR Part 316 (Orphan Drugs) contains the specific section (section 316.30) requiring the annual reports of holder of orphan drug designation:

§ 316.30 Annual reports of holder of orphan-drug designation.
Within 14 months after the date on which a drug was designated as an orphan drug and annually thereafter until marketing approval, the sponsor of a designated drug shall submit a brief progress report to the FDA Office of Orphan Products Development on the drug that includes:
(a) A short account of the progress of drug development including a review of preclinical and clinical studies initiated, ongoing, and completed and a short summary of the status or results of such studies.
(b) A description of the investigational plan for the coming year, as well as any anticipated difficulties in development, testing, and marketing; and
(c) A brief discussion of any changes that may affect the orphan-drug status of the product. For example, for products nearing the end of the approval process, sponsors should discuss any disparity between the probable marketing indication and the designated indication as related to the need for an amendment to the orphan-drug designation pursuant to § 316.26.

EU has the similar requirement and sponsors are required to submit to the European Medicines Agency (EMA) every year after their medicine has been granted orphan designation. See EMA Orphan Designation Annual Report.

PSUR: Periodic Safety Update Reports

The term PSUR comes from the previous ICH E2C (R1) “Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs”. ICH guideline E2C has been subsequently revised and renames as Periodic Benefit-Risk Evaluation Report (PBRER) (see below). However, the term PSUR is still used by EMA. See EMA's 'Periodic safety update reports: questions and answers'

PBRER: Periodic Benefit-Risk Evaluation Report

According to the ICH E2C (R2) “PERIODIC BENEFIT-RISK EVALUATION REPORT (PBRER)”,

The Periodic Benefit-Risk Evaluation Report (PBRER) described in this Guideline 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.

Other supporting documents regarding PBRER are:

• Concept Paper
• Business Plan
• Contribute to the E2C(R2) IWG

E2C (R2) is finalized at November 2012 and is supposed to replace the PSUR. However, EMA has not fully adopted the PBRER and continues to use the term PSUR as defined in its recent guideline “Guideline on good pharmacovigilance practices (GVP) 4 Module VII – Periodic safety update report (Rev 1)”

FDA fully endorsed E2C (R2) and PBRER and issued its guidance “Providing Postmarket Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report”

A paper EMA’S NEW PSUR-PBRER from Sentrx.com discussed this confusion.

PBRER vs. DSUR

It is often confusing whether or not a PBRER or DSUR or both are needed. It is commonly understood that PBRER is for a marketed products (including approved drugs that are under further study) and DSUR is for drugs under development (including marketed drugs that are under further study). In US, for the marketed products, if IND is still open, the annual safety report (i.e., DSUR) will be required by FDA.

There are some duplications between the DSUR and PBRER. FDA's guidance "PERIODIC BENEFIT-RISK EVALUATION REPORT (PBRER)" intended to provide some clarifications about PBRER and DSUR. In some situations, both PBRER and DSUR are required (to meet different regulatory requirements). in preparation. However, the effort can be made to minimize the duplicate works.

"This guideline aims to address this duplication and facilitate flexibility by encouraging the use of individual modules, where they pertain to more than one report – to be used at different times, for different authorities, and for different purposes. Therefore, the PBRER has been developed in such a way that content of several sections may be used for sections of other documents as a basis for a modular approach (see Section 1.1). "

To some degree, the DSUR can be considered as a subset of PBRER with focus on the ongoing clinical trials.