Now that Drug Safety Update Reports (DSURs) are in full force in the EU and elsewhere and, now that they are being accepted by FDA, it is time to take a look at DSURs and the issues and strategies around them. In particular, should a company submit a DSUR or an Annual Safety Report to the FDA?
Although recently coming into force in various regions, the idea of the DSUR is rather old going back to CIOMS VI/VII and ICH E2F in the early and mid 2000’s. It came into effect in the EU about 2 years ago and is accepted (but is not obligatory) by FDA. See the E2F document at https://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.
What is a DSUR?
The DSUR is the pre-marketing equivalent of the post-marketing Periodic Safety Update Report (PSUR). It covers drugs, biological, vaccines and combo products. It is a stand-alone document that is not just a data dump but is an analytical document. It should be “clear and succinct” (as all documents should be but rarely are). Its goal is the assessment of risk and any changes in risk since the previous DSUR. It also notes actions taken to reflect new or ongoing risks. The document is submitted to regulatory agencies and sometimes also to Ethics Committees/IRBs.
There should be only one DSUR for one investigational drug (active moiety) – no matter whether there are different formulations, indications etc. This is different from the US where each IND usually requires an annual report even if it is for the same drug (though FDA sometimes allows combining the several INDs into a single annual report submitted to more than one IND).
There should be only one DSUR used everywhere around the world. This, unfortunately, is not the case. Additional sections may need to be added for particular countries such as the US (see below).
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. However, think carefully about this in terms of operational resources. If the DSUR and PSUR are each large documents full of much data and detailed analyses, the company may not be able to write two large documents with the same submission date. A careful analysis of the internal resources needed for a simultaneous DSUR and PSUR should be made before committing to a harmonized submission of both every year.
The DSUR contents include:
- Executive Summary
- Table of Contents
2. Worldwide marketing authorisation status
3. Actions taken for safety reasons
4. Changes to the IB (reference document)
5. Status of ongoing and completed interventional trials during reporting period
6. Estimated exposure
- Clinical trials
- Marketed exposure
7. Line listings & summary tables
- General considerations
- SAR line listing table – for this reporting period
- SAE line listing table – cumulative
- Drop outs due to safety issues
8. Significant findings from clinical trials
- Completed & interim data
- Other uses
- Combination therapy if any
9. Relevant findings from non-interventional trials
10. Relevant findings from other sources
11. Safety findings from marketing experience
12. Other information
- Non-clinical data
- Long term follow up
- Other DSURs
- Significant manufacturing changes (for US)
- Lack of Efficacy
- Phase I protocol modifications (for US)
- Plan for upcoming year (for US)
13. Late breaking news
14. Overall safety evaluation and analysis
- Evaluation of risks
- Benefit risk considerations
15. Summary of important risks
The new concepts and pieces of this document compared to the old EU Annual Safety Reports and the current US Annual Reports are primarily in the overall safety evaluation and the summary of important risks sections.
Overall safety evaluation/Benefit-risk considerations
This section is a succinct statement describing the perceived balance between identified risks and anticipated efficacy/benefits. Any changes in this balance since the previous DSUR should be noted.
Summary of Important Risks
This section is a concise, cumulative issue-by-issue list of identified and potential risks (which are defined as those that might lead to warnings, precautions or contraindications in the labeling). These risks include issues based on a particular molecular structure or drug class, or concerns based on accumulating non-clinical or clinical data. Each risk must be reevaluated annually and addressed in the DSUR as appropriate with new information highlighted. A more detailed review should be done in early development of a drug when risks are less well characterized.
After the conclusions section, there are several appendices including:
- Investigator’s Brochure (if required locally)
- Cumulative Table of Important Regulatory Requests
- Status of Ongoing and Completed Clinical Trials
- Cumulative Summary Tabulations of Demographic Data
- Line Listings of Serious Adverse Reactions
- Cumulative Summary Tabulation of Serious Adverse Events
- Scientific abstracts (if relevant)
- Regional appendices such as a cumulative table of SARs, subjets who died or dropped out of studies, phase I modifications (US requirement), manufacturing changes, plan for the upcoming year (US requirement) and other IND issues (US requirement).
This is the “official” description covering the DSUR. Further information for the EU is available in an FAQ from the Heads of Medicines Agencies website on DSURs: https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2011_12_22_Q___A_DSUR.pdf
These Q&As give very useful information. Some of the key points are summarized here:
Q: When do you start preparing a DSUR?
A: After the first authorization of a clinical trial anywhere in the world. This also creates the Developmental International Birthdate (DIBD) for the drug. The DIBD of an authorized drug is the IBD (International Birth Date), the date when the product was first authorized in any country of the world. The submission dates for DSURs PSURs may also be harmonized. The first DSUR may be submitted anytime within one year after this birthdate but not longer than 1 year after the birthdate.
Q: When do you stop preparing DSURs?
A: The document indicates that there is ambiguity here in the regulations. The Heads of Medicines have concluded in this document that a DSUR should be submitted until the last visit of the last patient in the country(ies) concerned. If the trial has ended in a particular member state the DSUR does not have to be submitted there – only in countries where the study is still actively continuing. If there are several trials going on in that country, the DSUR must be submitted till the last patient’s last visit in the last study.
Q: Is a DSUR required for a trial lasting less than 1 year?
Q: Is a DSUR required for phase IV clinical trials if these are the only trials being conducted?
A: Yes. For investigator-initiated trials (IITs) a simplified document may be filed. See the Q&A for more details. If several IITs are being run at independent sites one single DSUR should be prepared. Member states may grant waivers to this if it is appropriate that more than one DSUR be submitted.
Q: Is a DSUR required for comparator and placebo products?
A: No a separate DSUR is not required but relevant safety information on the comparators should be addressed in the DSUR of the investigational drug. In certain sections (7.2, 2.7 and 3.7) of the DSUR all SAEs/SARs are required to be noted. The sponsor is encouraged but not obligated to provide relevant safety information to the MAH of the comparator products.
Q: What about the reference safety information if the SmPC is being used and not an IB?
A: The same SmPC should be used in all member states for the DSUR. If the SmPC (or IB) is updated during the period of the DSUR, the document in effect at the beginning of the reporting period should be used for DSUR preparation. Updating of the document(s) is not recommended during this time period however.
Q: Can the Company Core Safety Information (CCSI or CSI) be used as the reference safety information instead of an IB or SmPC?
A: Yes but only if it is part of the Investigator Brochure.
Annual Reports or DSURs to the FDA
Finally, FDA has indicated that it will accept DSURs instead of IND Annual Reports (76 Federal Register 52667 (23Aug2011) as long as they have all the requirements of the US Annual Report in the region specific appendices of the DSUR.
The question then is whether the sponsor should do an old style annual report or the DSUR. To a certain degree the answer to this is tactical and strategic. On the one hand, the DSUR is more complex and analytical than the old IND annual report which is largely a “data dump”. It requires the company to clearly delineate risks and then to come to a benefit risk conclusion. This requires more thought, time and analysis. This is presumably a good thing. On the other hand this requires more thought, time and analysis and risk description which, at least early in the development cycle, may be too preliminary, too inconclusive and perhaps even misleading and, for a small company with few resources, difficult to do. So what is the best or right thing to do? The narrow answer is that the sponsor will clearly obey the law by doing the old style annual report. The broader (and to my mind better) answer is that the sponsor as an ethical company working to improve the public health should do an analysis of the data and benefit/risk status and report this to the authorities.
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. It should be harmonized with other documents (PSURs, reference safety information etc.) and there is an international birthdate meaning that only one DSUR needs to be prepared in most cases. It is more complex and arguably preferable than the documents it replaces.