“DSURs are new, globally harmonised safety documents (which became obligatory in the Member States of the European Union in September 2011) covering the safety overview of pharmaceutical products during their production process or clinical trials.
The new DSUR (defined in the ICH E2F Guideline) is heavily based on the PSUR format already used to update drug safety records during their marketing process.
What is DSUR?
The development safety update report (DSUR) is pre-marketing periodic report that covers safety information of drugs, biological, vaccines and combo products under development (including marketed drugs that are under further study) among the ICH regions.
DSUR for single active moiety and combined products:
A single DSUR including safety data from all clinical trials conducted with the drug should be prepared for an investigational drug:
- All indications
- All intended populations
- All dosage forms
For combined products: For clinical trials involving a fixed combination product ( i.e., a product consisting of at least two active ingredients in a fixed dose given in a single dosage form), a single DSUR should be prepared.
If the sponsor also performs clinical trials with individual component(s) of the fixed combination product, separate DSUR(s) for each component should be filed.
Objective of DSUR:
A DSUR’s main objective is to provide a detailed, thoughtful annual review and assessment of relevant safety information gathered during the reporting period relating to a drug under investigation, whether or not it is marketed, by:
- To analyse whether the information provided by the sponsor during the reporting period is consistent with prior knowledge of the safety of the investigational drug
- To identify potential safety problems that may affect the health of subjects in clinical trials
- To summarise the current understanding and management of potential and identified risks
- providing an update on the status of clinical investigation/development program and study results.
Scope of the DSUR
The DSUR’s key focus is on evidence and results from interventional clinical trials of drugs and biologics under review, whether they have a marketing licence or not.
The DSUR should include safety details from all current clinical trials and other studies conducted or completed by the sponsor during the review period including:
- Clinical trials using an investigational drug (i.e. , human pharmacology, therapeutic exploratory and confirmatory therapeutic trials (phase 1–3))
- Clinical trials performed using marketed products in approved indications (i.e., therapeutic usage trials (phase 4);
- Usage of an investigational drug therapeutically (e.g., expanded access programs, compassionate use programs, particular patient use, single patient INDs, and treatment INDs); and
- Clinical trials conducted in order to support changes in the manufacturing process of medicinal products.
The DSUR includes safety information of active moiety from:
1. Both on-going clinical trials and other research performed or completed by the sponsor during the review period
2. Epidemiological or observational research
3. Nonclinical (toxicological and in-vitro trials) studies
4. Linked DSURs, if applicable to study drug
5. Formulation or microbiological modifications
6. Studies reviewed recently in the Literature
7. Clinical trials with findings suggesting lack of effectiveness that may have a direct impact on the protection of the subject ( e.g., worsening of the underlying condition if the indication is severe or life-threatening)
8. Any other valid source of safety results for products of the same therapeutic class.
9. Clinical trials carried out by a co-development partner, if the contractual arrangement permits
A DSUR should be concise and provide information to assure regulators that sponsors are properly monitoring and analysing the investigational drug’s changing safety profile.
All safety issues found during the reporting period should be addressed in the DSUR text; however, they should not be used to provide initial notice of important new safety information or to provide the means for detecting new safety issues
When to submit DSUR:
There is a single, harmonized Developmental International Birthdate (DIBD) which is the sponsor’s first permission from a regulatory agency to do a clinical trial anywhere in the world.
This will enable the company’s administrative committee to send this information to all of the health departments involved to harmonise the birthdate.
Since there is a known fixed schedule for the submission, there will be a fixed, single data lockpoint 60 days before submission for each DSUR.
Annually the DSUR is submitted in most countries. Companies with open INDs and NDAs (or ex-US equivalents such as CTCs / CTXs and MAs respectively) can also make their regulatory departments harmonise the birthdate for DSURs and PSURs in such a way that a single date for submission is available.
Recipients of DSUR
The DSUR is intended to serve as an annual report to regulatory authorities. Where national or regional laws or regulations require submission of an annual safety report on an investigational drug to ethics committees/institutional review boards, the DSUR Executive Summary might be appropriate, supplemented with line listings of serious adverse reactions (SARs) as warranted.
Therefore, it is concluded that DSUR is intended to serve as an annual report to:
- Regulatory Authorities: DSUR; within 60 days from the DIBD
- EC/IRB, if required: Executive Summary (plus line listing of SADRs)
- Final DSUR in a Territory: will be notified with a cover letter.
Format and Presentation of DSUR
The format and content of the DSUR should follow the table of contents below.
For each heading where information is available, the information should be presented concisely; when no information is available, this should be stated. Guidance on the content of each section is provided below.
Table of Contents
- Worldwide Marketing Approval Status
- Actions Taken in the Reporting Period for Safety Reasons
- Changes to Reference Safety Information
- Inventory of Clinical Trials Ongoing and Completed during the Reporting Period
- Estimated Cumulative Exposure
- 6.1 Cumulative Subject Exposure in the Development Program
- 6.2 Patient Exposure from Marketing Experience
- Data in Line Listings and Summary Tabulations
7.1 Reference Information
7.2 Line Listings of Serious Adverse Reactions During the Reporting
7.3 Cumulative Summary Tabulations of Serious Adverse Events
- Significant Findings from Clinical Trials during the Reporting Period
8.1 Completed Clinical Trials
8.2 Ongoing Clinical Trials
8.3 Long-term Follow-up
8.4 Other Therapeutic Use of Investigational Drug
8.5 New Safety Data Related to Combination Therapies
- Safety Findings from Noninterventional Studies
- Other Clinical Trial/Study Safety Information
- Safety Findings from Marketing Experience
- Nonclinical Data
- Other DSURs
- Lack of Efficacy
- Region-Specific Information
- 17. Late-Breaking Information
- Overall Safety Assessment
18.1. Evaluation of the Risk
18.2. Benefit-risk Considerations
- Summary of Important Risks
- Appendices to the DSUR
When to stop submitting a DSUR?
In Europe, an annual safety report is to be submitted to Member States in whose territory the CT is being performed during the clinical trial (CT) (Clinical Trial Directive 2001/20 Article 17(2)).
In general terms, when the trial ends, the application should cease. Yet there seem to be three different interpretations:
• The description of a completed trial for DSUR purposes is given in the ICH E2F glossary: ‘A clinical trial completed for which a final report of the clinical study is available. For DSUR purposes a trial for which enrollment has started and a final report of the clinical research is not available is considered to be ongoing.’
This will require a DSUR to be sent to the member states (MS) concerned before the final report of the clinical trial is completed and its summary sent to those European MSs.
• The end of CT in the protocol is to be specified specifically and unambiguously according to CT1 (2.5). In most cases this will be the last patient’s date of last visit.
• CT‐3 Guidance paragraph 126 reads: ‘The report should only be submitted to the competent national authority and to the Ethics Committee if there is ongoing treatment of subject matter in that Member State.’
That means DSUR is to be submitted in the MS concerned until the end of the treatment of the last subject.
To harmonise ICH E2F, CT1 and CT3, the ‘treatment of subjects is ongoing’ interpretation is that this clinical trial has not yet been completed.
Therefore a DSUR should be submitted as stated in the protocol until the last visit of the last patient in the MS concerned.
And a DSUR should be submitted only to the MS(s) concerned in which the territory of the clinical trial has not yet finished, no submission in order to the MS(s) concerned where the clinical trial has already been completed.
In the case of multiple studies approved during the reporting period by the MS concerned, a DSUR must be submitted in this specific MS before the last open CT (LVLP) has come to an end.
The DSUR is a document now agreed in most countries of the world that is more or less harmonised. It is a more detailed, comprehensive document than the annual safety reports.
See the E2F document at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500097061.pdf . This document is a must read if you prepare DSURs.
Relation of the DSUR to the Periodic Safety Update Report
When clinical trials continue after accepting market approval, both DSUR and PSUR are needed separately.
DSUR data lock point (DIBD)agree with the International Birth Date (IBD) if desired by sponsor.
Some ICH countries and regions currently recognise the submission of a Periodic Safety Update Report (PSUR) to satisfy national and regional standards for periodic safety monitoring of approved drugs.
Although the DSUR ‘s emphasis is on investigational drugs, the content of the DSUR and PSUR can overlap, and some repetition is predicted.
For example, information from marketing experience (reported in the PSUR) may be relevant to the clinical development, and therefore reported in the DSUR.
Safety results from clinical trials using marketed drugs would be included in the DSUR, but would also be applicable to the safety of post-marketing and would be recorded in the PSUR.
Both the DSUR and the PSUR should be detailed and stand-alone as they focus on different subjects and have different recipients and periodicities.”