DSUR (Developmental Safety Update Report)
DSUR which is prepared while the product is still in development phase, which stands for Developmental Safety Update Report. We can also call it as a pre-marketing equivalent of a PSUR (Periodic Safety Update report).
Before we go to the core of content and format, first let’s understand what a DSUR is?
DSUR is an internationally harmonized, safety document which covers the safety summary of investigation products during their development or clinical trial phase. This means that all new drugs under development that are currently undergoing a clinical trial must submit a DSUR to the regulatory authorities.
Now you might be wondering, why do we come across DSURs for medicines which are already on the market. There will also be instances where a product is already on the market, but the sponsor/MAH (Marketing Authorization Holder/Pharma Company, wants to further evaluate the drug; for example, for a new dose, new formulation or a new indication that is not covered by the drugs approved marketing status. In that case, the sponsor must submit DSUR until the clinical trials for a marketed drug are ongoing.
What are the objectives of a DSUR? The purpose of a DSUR is to provide a comprehensive annual analysis of the safety summary collected during the clinical trial. You may consider the document as a communication to the regulators about adequate monitoring and evaluation of a safety profile of a drug under investigation.
What is the scope of products for a DSUR? A DSUR may be required for any of the following
- Investigational drugs
- Investigational Biologicals
- Investigational Vaccines
- Combination products under investigation.
Clinical trials using an
investigational drug
Clinical trials conducted
to support changes in the manufacturing process of medicinal products
Clinical trials conducted
using marketed drugs in approved indications
Therapeutic use of an
investigational drug
What is DIBD?: - Developmental international Birthdate (DIBD) – it is the date of first authorization from a regulatory agency to the sponsor to conduct any clinical trial for an investigational product anywhere in the world.
How long is it to be submitted?- A DSUR is to be submitted as long as the clinical trial is ongoing. When submission of an annual report is no longer required in an individual country or region, the sponsor should indicate that the final DSUR serves as the last annual for the investigational drug in that country or region.
What is the frequency of a DSUR submission?- Usually the DSUR is submitted annually (the frequency may vary occasionally as per national or regional regulatory requirement).
The first DSUR should have a data lock point which should be within a year of its DIBD.
Also note that the DSUR is to be submitted to the regulatory authorities within 60 calendar days after the DSUR data lock point.
What is the reference safety document for a DSUR? Unlike PSUR, in case of DSUR the IB i.e. the Investigators Brochure stands as a reference document for the DSUR report.
The Format and Content is described in International Conference on Harmonization (ICH) guideline E2F.
Each section of DSUR is highlighted in the table below, along with a brief overview of what each section entails.
DSUR | PSUR | Comment for ease of understanding |
Part I | Title Page | Information about company, author of DSUR, Reviewers , data period etc |
Part II | Executive Summary | Snapshot of DSUR , summary of risk-benefit of product |
1 | Introduction | - DIBD and Reporting period - Details of investigational drug- mechanism of action, therapeutic class, dose, route, and formulation, indication etc |
2 | Worldwide Marketing Authorization Status | - Date of first approval - Indication(s), approved dose(s), and countries where approved, if applicable. |
3 | Actions Taken In the reporting interval for Safety Reasons | - Significant safety related actions taken during the reporting period along with reasons for each action. e.g. Regulatory authorities requested hold on clinical trials, withdrawal of product etc |
4 | Changes to Reference Safety Information | Significant safety-related changes to the Investigators Brochure OR USPI or other such RSI documents within the reporting period. |
5 | Inventory of clinical trials ongoing and completed during the reporting period | - Overview of the clinical trials ongoing and completed by the sponsor during the reporting period. |
6 | Estimated Cumulative Exposure 6.1 Cumulative Subject Exposure in the Development Programme 6.2 Patient Exposure from Marketing Experience | - Sections 6.1 and 6.2 of the DSUR should provide information on cumulative exposure in clinical trials and the marketed setting, respectively. |
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 | This should present important clinical safety information through line listings (cumulative and reporting period) |
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 | - Each sub section should provide a brief summary of clinically important emerging efficacy and safety findings from clinical trial |
9 | Safety Findings from Non Interventional Studies | - Relevant safety information from sponsored or co-sponsored non-interventional studies (e.g. observational studies, epidemiological studies, active surveillance programmes) |
10 | Other Clinical Trial/Study Safety Information | - Relevant safety information from any other sponsored or co-sponsored clinical trial/study sources (e.g. results from pooled analyses or meta analyses of randomized clinical trials) |
11 | Safety Findings from Marketing Experience | - Applicable in case investigational drug has been approved for marketing in any country - Should provide a summary of key safety findings that have arisen from marketing experience. |
12 | Nonclinical Data | - Major safety findings from non-clinical in vivo and in vitro studies (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the reporting period. |
13 | Literature | - New and significant findings, either published in the scientific literature or available as unpublished manuscripts, relevant to the investigational drug during the reporting period. |
14 | Other DSURs | - In case, multiple DSURs are to be prepared for a single investigational drug, this section should summarise significant findings from other DSURs. . |
15 | Lack of Efficacy | - Data indicating lack of efficacy for investigational drugs intended to treat serious or life-threatening illnesses (e.g. excess cardiovascular adverse events in a trial of a new antiplatelet drug for acute coronary syndromes) |
16 | Region-Specific Information | - The information in this section can be used to comply with national or regional requirements and can be provided in appendices to the DSUR. |
17 | Late-Breaking Information | - Important safety findings that arise after the data lock point but while the DSUR is in preparation. |
18 | Overall Safety Assessment 18.1. Evaluation of the Risks 18.2 Benefit-risk Considerations | - Concise, integrated evaluation of all new relevant clinical and non-clinical and epidemiological information obtained during the reporting period relative to the previous knowledge of the investigational drug. |
19 | Summary of Important Risks | - Concise, cumulative, issue-by-issue list of important identified and potential risks. |
20 | Conclusions | - Changes to the previous knowledge or efficacy and safety since the last DSUR. |
To summarize, DSUR is a complex and analytical document that should be utilized to analyze risk and safety profile of product in an ongoing manner.
References:
1. FDA
2. EMA
Written by:
Dr.Shraddha Bhange.
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