27. Development safety update report (DSUR)

What is a DSUR?

The development safety update report (DSUR) is pre-marketing periodic report which 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:

1. All indications
2. All dosage forms
3. All intended populations

For combined products: A single DSUR should be prepared for clinical trials involving a fixed combination product (i.e., a product consisting of at least two active ingredients in a fixed dose that is administered in a single dosage form). If the sponsor is also conducting clinical trials with individual component(s) of the fixed combination product, separate DSUR(s) should be submitted for each component. 

Objective:

The main objective of a DSUR is to present a comprehensive, thoughtful annual review and evaluation of pertinent safety information collected during the reporting period related to a drug under investigation, whether or not it is marketed, by: 

• examining whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the investigational drug’s safety 
• describing new safety issues that could have an impact on the protection of clinical trial subjects
• summarizing the current understanding and management of identified and potential risks
• providing an update on the status of the clinical investigation/development program and study results. 

The DSUR includes safety information of active moiety from:

1. All ongoing clinical trials and other studies that the sponsor is conducting or has completed during the review period
2. Observational or epidemiological studies 
3. Nonclinical studies (toxicological and in vitro studies) 
4. Related DSURs, if applicable to the investigational drug
5. Manufacturing or microbiological changes
6. Studies recently published in the literature 
7. Clinical trials with results indicating lack of efficacy that could have a direct impact on subject safety (e.g., worsening of the underlying condition if the indication is serious or life-threatening) 
8. Any other source of relevant safety findings for products in the same therapeutic class 
9. Clinical trials conducted by a co-development partner, if permitted by the contractual agreement.

When to submit DSUR: 

There is a single, harmonized Developmental International Birthdate (DIBD) which is the first authorization from a regulatory agency to the sponsor to do a clinical trial anywhere in the world.  This will require the regulatory group in the company to convey this information to all of the involved health agencies so that the birthdate is harmonized.  Since there is a known fixed schedule for submission, there will be a fixed, single data lockpoint 60 days before submission for each DSUR.  

In most countries the DSUR is submitted annually. Companies that have open INDs and NDAs (or the ex-US equivalents such as CTCs/CTXs and MAs respectively) may also have their regulatory departments harmonize the birthdate for DSURs and PSURs such that there is a single submission date. 

DSUR and PSUR:

When clinical trials continue after receiving market approval, both DSUR and PSUR are needed separately.

DSUR data lock point (DIBD) can coincide with the International Birth Date (IBD) if desired by sponsor.

Recipients of DSUR

• 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.

DSUR Contents

Title page

Executive Summary

Table of Contents 

1. Introduction 
2. Worldwide Marketing Approval Status 
3. Actions Taken in the Reporting Period for Safety Reasons 
4. Changes to Reference Safety Information 
5. Inventory of Clinical Trials Ongoing and Completed during the Reporting Period 
6. Estimated Cumulative Exposure 
   • 6.1  Cumulative Subject Exposure in the Development Program 
   • 6.2  Patient Exposure from Marketing Experience 
7. Data in Line Listings and Summary Tabulations 

• 7.1  Reference Information 
• 7.2  Line Listings of Serious Adverse Reactions During the Reporting
  Period 
• 7.3  Cumulative Summary Tabulations of Serious Adverse Events 

8. 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 

9. Safety Findings from Noninterventional Studies 

10. Other Clinical Trial/Study Safety Information 

11. Safety Findings from Marketing Experience 

12. Nonclinical Data 

13. Literature 

14. Other DSURs 

15. Lack of Efficacy 

16. Region-Specific Information 

17. Late-Breaking Information 

18. Overall Safety Assessment 

• 18.1. Evaluation of the Risks 
• 18.2 Benefit-riskConsiderations 

19. Summary of Important Risks 

20. Conclusions 

Appendices to the DSUR 

When to stop submitting a DSUR?

In Europe an annual safety report is to be submitted throughout the clinical trial (CT) to Member States in whose territory the CT is being conducted (Clinical Trial Directive 2001/20 Article 17(2)).

Generally speaking, the submission should stop when the trial ends. However there seems to be 3 different interpretations:

• The definition of a completed trial for DSUR purposes is given in the ICH E2F glossary: ‘Study for which a final clinical study report is available is a completed clinical trial. For DSUR purposes a trial for which enrolment has begun and a final clinical study report is not available, is considered to be ongoing.’

This would mean a DSUR needs to be submitted to the concerned member states (MS)s until the final clinical study report is completed and its summary submitted to these European MSs.

• According to CT1 (2.5), the end of CT is to be defined clear and unambiguous in the protocol. In most cases it will be the date of last visit of last patient.

• CT‐3 guidance paragraph 126 reads: ‘The report should only be submitted to the national competent authority and the Ethics Committee if the treatment of subjects is ongoing in that Member State concerned.’

Meaning that DSUR is to be submitted until the end of treatment of the last subject in the MS concerned.

In order to harmonise ICH E2F, CT1 and CT3, the interpretation of the ‘treatment of subjects is ongoing’ is that this clinical trial has not ended yet.

Therefore, a DSUR should be submitted until the last visit of the last patient in the MS concerned, as specified within the protocol.

And a DSUR should only be submitted to the concerned MS(s) on which’s territory the clinical trial has not ended yet, no submission in needed to the concerned MS(s) where the clinical trial ended already.

In the case of multiple studies being authorised by the concerned MS within the reporting period, a DSUR must be submitted until the last open CT has come to an end (LVLP) in this concerned MS.

The DSUR is a more or less harmonized document now accepted in most of the countries of the world.  It is a more complex and analytical document than the old style annual safety reports.  

Refer https://database.ich.org/sites/default/files/E2F_Guideline.pdf for detailed guidelines on contents.