Pharmacovigilance Trends: Getting to Know the DSUR

In 2010, the International Conference on Harmonization (ICH) rolled out its E2F Development Safety Update Report (DSUR) guideline. The DSUR is similar to the US’s Investigational New Drug Annual Report (IND-AR) and the EU’s Annual Safety Report (ASR) in that its purpose is to provide a brief overview of safety for a project on an annual basis. Although both the Food & Drug Administration (FDA) and EU Clinical Trial Directive required what is termed as IND AR and ASR, respectively, the content, format and timings differed between the US and EU reports. Considering that most contemporary trials are multinational, a need was felt towards harmonizing these requirements and to provide a uniform standard acceptable to all regulatory agencies across the world. The concept of a DSUR was first introduced by the CIOMS VI working group and taken forward by the CIOMS VII working group. In 2008, the ICH published a draft guideline E2F on DSUR, which has been updated in August, 2010, incorporating background, objective and scope of DSUR and providing guidance on DSUR contents.Major features of the DSUR are that it covers an entire Investigational Medicinal Product (IMP) rather than just an indication, and that much of its information is cumulative from inception of the project.     

FDA’s planned updates for Module 1

Among these is a new Section 1.13.15, for the DSUR, but FDA’s Module 1 update is not expected to be implemented until early 2013.  As per Connie Robinson (FDA personnel), “Currently for an IND, it would be acceptable to place the DSUR as a single document in Section 1.13.3 Summary of Safety Information. You should state that the DSUR is being submitted in place of the IND annual report in the cover letter and provide a link to the document if possible. If information (other than the granular annual report information) is expected as a part of the DSUR, but the information should be placed in its own designated e-CTD location.”

Usefulness of DSUR

DSURs, which are an enhanced report over the previous required reports, contain not only an evaluation of safety information collected in the past year but also includes a cumulative review of existing safety information. This evaluation allows the sponsors the ability to identify and evaluate potential risks with the drug and make appropriate adjustments to their clinical development program.The DSUR expects more information than its predecessors (IND-ARs and ASRs) including patient data from the inception of a project, and could thus take more time for a company to prepare. As with most things, once a process is put in place and becomes familiar, subsequent reports will become smoother to produce.

Points to Remember

1.      A DSUR should be submitted until the last visit of the last patient in the Member States concerned, as specified within the protocol.

2.      The data lock point (DLP) for a DSUR reporting period is the last day (or the last day of the month, ICH E2F section 2.2) before the anniversary of the DIBD (Development International Birth Date), the date on which the product was first authorized for testing in humans anywhere in the world. IBD (International Birth Date), the date on which the product was first approved for market anywhere in the world can also be acceptable.

3.      The first DSUR period should not be longer than 1 year. The DSUR is always submitted on a yearly basis.

4.      For transitional period: The DIBD and the European Birth Date (EBD) of the previous

5.      ASR should be aligned in such a way that DSUR periods that are substantially longer than 12 month as well as overlapping DUSR periods are avoided.

6.      A DSUR is required for Phase IV clinical trials, if only such trials are conducted.

7.      Submission of one single DSUR is strongly recommended if the same IMP is used in the clinical trials.

8.      A separate DSUR for a comparator, placebo or non-IMP is not required. However, relevant safety information of the above mentioned drug types should be addressed in the DSURs of the investigational drugs.

9.      The Investigator Brochure (IB) or Summary of Product Characteristics (SmPC) can be updated during the DSUR reporting period.

Since CDSCO does not require DSUR, for Indian pharmaceutical companies undertaking a global trial for a locally developed drug, Indian regulators will not have real-time update of the drug's developing safety profile, while foreign regulators (such as tripartite countries) having requirement of DSURs will have this information. With the global focus on DSUR, Schedule Y needs to be revised incorporating similar provision of providing cumulative safety updates to the regulators during clinical development phase.