BW706 Blog #4

Theresa Seiverd
Blog #4
1. Name of Guidance: E2F: Development Safety Update Report

2. Status of Guidance: Draft

3. Release Date: 05 June 2008

4. Link to Guidance: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129284.pdf

5. Target Audience: Pharmaceutical companies (sponsors)

6: Laws and Regulations Referenced: 21 CFR312.33: Investigational New Drug (IND) Application Annual Reports and EU Directive 2001/20/EC on Clinical Trials

7: Summary: The Development Safety Update Report (DSUR) is annual summary of safety information for investigational drugs (ie, drugs that are administered in clinical trials). It is considered critical information for the ongoing assessment of the risk to trial participants during the clinical development of a new drug. The goal for developing the DSUR is to create a common standard among the International Conference of Harmonization (ICH) regions for reporting annual safety information that will promote a consistent approach to reporting, and also make the current reporting structure more efficient. The intent is to have the DSUR replace the US IND Annual Report and the EU Annual Safety Report (ASR).

8. Rationale: It makes sense to consolidate similar reports required by different regions into 1 report that would satisfy all regions. The DSUR is also the complimentary document to the Periodic Safety Update Report (PSUR). Both the DSUR and PSUR will have some overlap, but the DSUR focuses on pre‑approval conditions and the PSUR focuses on post-approval conditions Therefore, the development of the DSUR made sense from a transitioning standpoint for the development of a n integrated life-cycle approach between the 2 documents in transitioning from preclinical to post approval stage.

9. Recommendation: It is recommended that the DSUR be adopted by industry as the common global standard for reporting safety data for clinical trials for a single drug product during a standard reporting period on an annual. If a sponsor has more than 1 drug in clinical trials than it is recommended that a DSUR be prepared with a single data lock for all trials. Submission of the DSUR should be no later than 60 calendar days after the data lock point. Once a drug receives marketing approval the data lock point must align with the International Birth Date (IBD) so the DSUR and PSUR can be synchronized. The guidance provides a template of sections that the DSUR should contain. The sections are outlined below and should be written as concise as possible. If there is no information to report for a certain section, this should be stated below the header to keep it organized and follow the template provided.

• Introduction: The introduction should include the dates of the reporting period, a brief description, its mode of action, route of administration, and formulation. It should provide the active trials during the reporting period, the indication(s) being studied and the population.
• Worldwide Marketing Authorization Status: If a marketing application has been submitted in 1 or more countries or regions then this section should be completed, and a status update for each country or region provided. The PSUR has a similar section and the format for that section can be followed here.
• Update on Actions Taken in the Reporting Period for Safety Reasons: A description of any significant safety related actions taken by the sponsor, regulator, or safety monitoring board’s needs to be disclosed and reported in the section. It applies to both the clinical development and marketing product if a product a drug has received approval.
• Changes to Reference Safety Information: Any safety related changes to the investigator brochure during the reporting period is required.
• Status of Clinical Trials Ongoing and Completed During the Reporting Period: This section typically has a table for each ongoing and completed trials of the reporting period. It includes information that describes the trial, dose regimen, countries with active sites, enrollment numbers, exposure numbers, and other pertinent information of the trial.
• Estimated Exposure: This section describes the method used to estimate subject exposure during the reporting period. Data should be presented by indication if available.
• Presentation of Safety Data from Clinical Trials: This section should include general information about the line listings of all serious adverse events for each clinical study and the criteria used for inclusion. It should reference the reader to the appropriate appendices.
• Significant Findings from Clinical Trials during the Reporting Period: This includes ongoing and completed trials during the reporting period. If any significant safety information becomes available for any trial than it needs to be included.
• Relevant Finding s from Non-interventional Studies: This section takes into account information that is learned from observational studies whereby the sponsor is not responsible for providing the drug (or intervention) to the subject. Non-interventional studies would include the Phase 4 registry studies, surveillance programs, or epidemiological studies.
• Relevant Findings from Other Sources: This may include results from meta-analyses or trials with vaccines.
• Safety Findings from Marketing Experience: If an investigational drug is approved in any country a concise summary of key findings should be reported. Especially if the findings resulted in changes to the label or risk management plan.
• Other Information: If there are any safety findings from non-clinical in vivo or in vitro studies then it needs to be reported. Or, if there is new safety information on drugs of the same class then this information should also be included.
• Late-breaking Information: This would include any safety information that becomes available after the data lock point. It could be from a case study or information from a safety board or regulatory authority that becomes available.
• Overall Safety Assessment: This section should provide an interpretation of the information provided, and its implications to the subjects in the clinical trial population. It is important that certain categories (withdrawals, pregnancies, deaths, overdoses, laboratory evidence, drug-drug interactions) be monitored to identify a potential risk to the safety of the subject.
• Summary of Important Risks: A summary of any risks identified and how they will be managed needs to be provided in this section.
• Appendices to the DSUR: Line Listings of Serious Adverse Reactions for each study, and Aa cumulative tabulation of SAEs is recommended and would probably accompany a DSUR report.
  10. Impact: The concept of creating the DSUR is to reduce the number of similar documents that are submitted through separate regional health authorities, and create one document that will contain all information and meet all the regional health authority requirements. By accomplishing this goal of creating 1 document, it will make resourcing more efficient since the same people will not have to do multiple documents and can focus on 1 document. From the Regulatory side, it may also reduce review time since multiple documents with similar information will not have to be reviewed.