Development Safety Update Report (DSUR) and the ICH Guidance

Introduction

Every investigational drug undergoes clinical developmental stages (e.g., Phase 1, Phase 2 and Phase 3), and the safety of the study subjects is a key concern in each clinical trial. Safety profiles of the subjects are always difficult to evaluate. Periodic assessment of safety information is also crucial to the ongoing risk assessment. Researchers are required to inform regulators and other stakeholders at regular intervals about the safety profiles with respect to the drugs.^1-3 However, because different countries' regulatory authorities require different content and use different formats and schedules, the International Conference on Harmonization (ICH) has developed guidelines for the Development Safety Update Report (DSUR), which is not only a common format for various countries, but also is designed to maintain the consistency and efficiency of an annual report and be broadly useful.^4,5

The objective of a DSUR is to present a comprehensive annual review and evaluation of safety information collected within the reporting period (pre- and postapproval of drugs, biologics and vaccines). Information should be reported based on the previous knowledge of a product's safety. Any new issues that may impact the overall program or specific clinical trials are required to be described in detail. At the same time, current understanding and management of known and potential safety risks to exposed patients are also summarized. Subsequently, any changes in a product's safety profile should be examined and an update on the status of the clinical development program should be provided.

The impact on the safety and welfare of clinical trial subjects (e.g., non-clinical or observational studies) is required to be assessed. Because clinical development of a drug frequently continues after marketing approval, relevant information from postmarketing studies also should be included in the DSUR. The DSUR should concentrate primarily on the investigational drug, providing information on comparators only where relevant to the safety of trial participants. The purpose of this article to shed light on ICH developed guidance on DSUR.⁶

Content and Timeline for a DSUR

A single DSUR is required to include safety data from all clinical trials conducted with the investigational drug using all indications, all dosage forms, and all intended populations. This includes multiple clinical trials, multiple sponsors if there is a formal agreement, and combination products (fixed combination drug, multidrug regimen trials).

The DSUR is intended to serve as an annual report with the data lock point (DLP) based on Development International Birth Date (DIBD), the date of the first authorization to conduct interventional clinical trials in any country, submitted to regulatory authorities within 60 days from the DIBD. If national or regional laws require the submission of an annual safety report on an investigational drug to an Ethics Committee or Institutional Review Board (IRB), the submission of the executive summary with line listings of serious adverse events (SAEs) might be appropriate.

The DSUR should provide safety information from all ongoing clinical trials and other studies that the manufacturer is conducting or has completed during the review period including⁷:

clinical trials using an investigational drug (both ongoing and completed)⁸
clinical trials conducted using marketed drugs in approved indications (i.e., therapeutic use trials (Phase 4))^{9   }
therapeutic use of an investigational drug
clinical trials conducted to support changes in the manufacturing process of medicinal products

The DSUR also should include significant other findings pertinent to the safety of the investigational drug, including findings from:¹⁰

observational or epidemiological studies
non-clinical studies
related DSURs, if applicable to investigational drug
manufacturing or microbiological changes
studies recently published in medical journals
clinical trials with results indicating lack of efficacy that could have direct impact on subject safety
any other source of relevant safety findings for products in the same therapeutic class
clinical trials conducted by co-development partner, if permitted by contractual agreement

The reference safety information is the Investigator Brochure (IB). Local product labels should also be used as reference safety information when an IB is not required.

There are two new sections in DSUR:(1), Actions taken in the reporting period for safety reasons, which includes a description of significant actions related to safety during the reporting period by the sponsors, regulators or data monitoring board; and (2), Summary of important risks, which should provide a concise, cumulative, issue-by-issue list of important identified and potential risks. Such risks might include toxicities known to be associated with a particular molecular structure or drug class or concerns based on accumulating non-clinical or clinical data. Each risk should be re-evaluated annually and summarized as appropriate, based on the current state of knowledge. New information should be highlighted. The appropriate level of detail is likely to be dependent upon the stage of drug development. For example, summaries covering drugs in early development might include information on each risk, which might be less detailed. The information in this section could provide the basis for the safety specification of a risk management plan (ICH E2F).¹¹ Risks that have been fully addressed or resolved should remain in the summary and be briefly described, e.g., findings from toxicology studies or early clinical trials that were not borne out by later clinical data. This information can be provided in either narrative or tabular format.

DSUR and PSUR

Since it is hard to evaluate and reevaluate the safety of individual cases, the periodic safety report (PSUR) was developed.¹² Furthermore, when clinical trials continue after receiving market approval, the submission of both DSUR and PSUR are needed separately. The DSUR data lock point can coincide with International Birth Date (IBD) if desired by the sponsor. A PSUR is a periodic report whereas a DSUR is annual. These reports are compared in Table 1. [media:1654:embed:left] 

DSUR and IND Annual Report

Submission of a DSUR is currently mandated only in the EU and accepted in the US in lieu of a US Investigational New Drug application (IND) annual report.¹³ When a US IND annual report is compared with a DSUR, several gaps are found, which are summarized here:

Individual Study information, which requires a brief summary of the status of each ongoing and completed study in the previous year for IND annual report, whereas a DSUR assembles all individual studies, but does not identify which one is under an IND, which one is an IRB waiver and which one is listed under www.clinicaltrials.gov . Moreover, a DSUR does not include non-interventional and long-term extension (LTE) studies, which are included under an IND.

Summary of Information consists of

narrative or tabular summary of most frequent and most serious adverse experiences by body system
summary of IND safety reports
list of subjects who died with cause of death
list of dropouts due to adverse events
mechanism of action
list of non-clinical studies
summary of significant manufacturing or microbiological changes

In contrast, a DSUR needs full data under IND for LTE studies. Registries and observational studies may or may not be under an IND. Moreover, it does not include non-clinical and manufacturing update with stability studies.

Recently, the US Food and Drug Administration (FDA) revised the comprehensive table of contents headings and hierarchy¹⁴ and added a new section 1.13.15 for DSURs.

Advantages and Disadvantages of DSURs

The advantages of submitting a DSUR are:

Not only does it harmonize clinical safety data management with pharmacovigilance, it also provides a current safety profile.
It decreases the number of reports.
It provides a comprehensive, thoughtful annual review and increased assurance of protection for the trial subjects.
The two new sections in the DSUR should provide a concise, cumulative, issue-by-issue list of important identified and potential risks.
Regulators and sponsors review the same information at the same time.

The disadvantage of using a DSUR is:

In order to complete the section "Action taken in the reporting period for safety reasons," large pharmaceutical companies that run many clinical trials in various countries have to collect the data related to safety from their affiliates within a very short period of time.

Conclusions

Due to different requirements in content, format and timing of the reports for the various countries' regulatory authorities, ICH developed guidance for an annual safety report known as DSUR, which provides a common format and maintains consistency among regulators. The DSUR report is concise and provides information from interventional clinical trials of investigational drugs, biologics or vaccines, including information about the safety and welfare of trial subjects (e.g., non-clinical and observational studies) to assure regulators that the manufacturers are adequately monitoring and evaluating the safety profile of investigational drugs.

A single DSUR contains safety data from all clinical trials conducted for the investigational drug using all indications, all dosage forms and all intended populations.

Both the PSUR and DSUR deal with worldwide safety. Both use cumulative drug exposure. The PSUR evaluates the safety of individual subjects, whereas the DSUR examines the safety of clinical subjects from interventional or non-interventional studies. Moreover, it deals with safety from market experiences, nonclinical, other DSURs, lack of efficacy, region-specific information and late-breaking information. When compared with an IND annual report, several gaps are found. Instead of replacing the IND annual report, FDA decided to add DSUR documents in section 1.13.15.

Overall, DSUR provides a safety profile of clinical subjects taken both from interventional and non-interventional studies. It improves consistency among companies and decreases the number of reports, reducing the burden for sponsors as well as regulators.

Reference

21 CFR 312.32 - IND safety reports.
Guidance for Industry : E6 Good Clinical Practice: Consolidated Guidance http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf
Guidance for Industry E2C Clinical safety Data management
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073102.pdf
Urushihara H and Kawakami K Development Safety Update Reports and Proposals for effective and efficient Risk communication Current Opinion Drug Saf 2010; 33(5):341-352
E2F Step 5 Note for guidance on development safety update report http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500097061.pdf
Urushihara, op. cit. 341-352
E2F. op. cit.
Ibid
Guidance. op. cit.
E2F. op.cit. Ibid.
Guidance. op. cit.
21 CFR 312.33 Investigation New Drug Application-Annual Report
The Comprehensive Table of Contents Headings and Hierarchy, version 2.1 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163175.pdf

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