The following topics are covered as fundamental concepts for Aggregate Safety Report (ASR) writing
The periodical reporting of aggregate safety reports to regulatory health authorities includes a comprehensive overview of the safety profile of medicinal product based on cumulative safety information accumulated by Marketing Authorization Holder (MAH) during the reporting intervals. They also provide assurance that the MAH is continuously monitoring and critically assessing the benefit-risk profile of the product and taking appropriate risk minimizing actions where new safety concerns or changes to existing safety issues are identified. The international standard for periodic reports follows reporting guidelines set by the International Conference on Harmonization (ICH).
In addition to submission of Individual case safety reports (ICSRs), MAH is obliged to report the cumulative safety exposure data in periodical intervals to respective health authorities within the specified timelines which in turn depends on age of medicinal product in the market and type of aggregate report. This continued monitoring on aggregate safety data facilitates regulators and MAH to maintain positive benefit risk balance and implementing the early risk minimization plans for the reported safety concerns.
Based on marketing authorization status, different types of reports are prepared by MAH, which include the pre-approval aggregate safety reports and post-approval aggregate safety reports.
Pre-approval aggregate reports: It includes the cumulative summary of safety information for molecules under clinical development. It usually includes safety information from non-clinical studies and safety data for the subjects participated in clinical trial.
- Annual safety reports (ASRs) in Europe
- Investigational New Drug (IND) annual reports in United States
However, these two documents were replaced by a well harmonized document, “Development Safety Update Report (DSUR)”, in which health regulators in the three ICH regions can receive the same information at the same time, thereby reducing the total number of reports generated.
Post-approval aggregate reports: They provide the cumulative summary of safety information for the medicinal products from the marketing exposure. The sources of safety data include Non-clinical, clinical studies and Non international studies, literature articles and spontaneous cases.
The following types of reports are submitted for medicinal products post marketing authorization.
- PADER (Periodic Adverse Drug Experience Report)
- Periodic Benefit Risk Evaluation Report (PBRER)/ Periodic Safety Update Report (PSUR)
- Addendum to Clinical Overviews (ACO)
- Risk Management Plan (RMP)
Marketing authorization holders are obliged to report the evolving safety profile of investigational medicinal product and actions taken or proposed for the new safety concerns identified during the development to the respective health authority and local regulatory bodies (e.g., Institutional review board and local ethics committee).
It should be submitted no later than 60 calendar days from the DSUR data lock point (DLP).
Developmental International Birth Date DIBD:
The Data Lock Point (DLP) or the cut off date for DSUR is stop date of reporting interval for a molecule from the date of authorisation for conducting a clinical trial which is called as developmental International birth date (DIBD).
In addition to the innovator molecules, DSURs are submitted for the marketed products also, which are in clinical trial for other unapproved therapeutic use, comparability studies and for marketed drugs with approved indication which required additional safety monitoring.
Periodic Adverse Drug experience report is a post-marketing safety report submitted to the United States Food and Drug Administration (USFDA). The main objective is to provide summary data with an assessment of an approved drug product’s benefit risk profile from the post marketing exposure. The scope of PADER is limited to serious and unlisted cases which include concise narratives and summary analysis of 15-day ICSR reports. It also includes the regulatory actions taken for safety reasons during the reporting interval since last submitted PADER.
The regulatory timelines for submission of PADERs to US FDA authority are depicted in the below table.
Regulatory timeline for PADER submissions
|Reporting Interval category||Criteria for medicinal products||Regulatory timeline|
|Quarterly||For First three years, after marketing authorization||30 calendar days|
|Annual||In market for more than 2 years||60 calendar days|
The Benefit-risk evaluation should be carried out throughout the life cycle of the medicinal product to promote and protect public health and to enhance patient safety through effective risk minimization plans and implementations. After a marketing authorisation is granted, it is necessary to continue evaluating the benefits and risks of medicinal products in actual use and/or long-term use, to confirm that the benefit-risk profile remains favourable.
International birth date (IBD):
The date when sponsor received authorisation for marketing a drug is considered as International birth date (IBD) of the medicinal product.
Data lock point is the cut-off date for completion of reporting interval. PBRER is a complex report with 20 sections including appendices compared to DSUR and PADER. The timeline for these post approval aggregate reports varies based on the age of medicinal product in the market which included the following kinds of reporting intervals and their respective regulatory timelines.
Regulatory timeline for PBRER submissions
|Reporting Interval category||Criteria for medicinal products||Regulatory timeline|
|6 month reporting interval||Newly approved and marketed for 1-year period||70 calendar days|
|Annual reporting interval||In market for more than 1 year||90 calendar days|
|Multi-layer reporting Interval||In market for more than 5 years||90 calendar days|
The comprehensive list of active substances and combinations of active substances contained in medicinal products subject to different marketing authorisation, together with the corresponding EU reference dates, frequencies for submission of periodic safety update reports and related data lock points could be obtained from the European Union reference dates (EURD) list. European Medicines Agency (EMA) updates the EURD list on monthly basis.
MAH can get relief in submitting PBRER/PSUR for the products which are well established, generic products in the market for longer time, homeopathic medicines and for traditional herbal medicines.
Addendum to clinical overviews are aggregate safety reports which are submitted to respective regulatory authorities for renewal of marketing authorization license of a medicinal product. They include the benefit-risk balance of the medicinal product based on the clinical data. The structure and specifications of the ACO and PBRER are similar. But the information presented with greater emphasis on the data received since the last renewal/approval rather than discussing cumulatively.
In addition, the history of Pharmacovigilance system inspections (date, inspecting authority, site inspected, type of inspection and if the inspection is product specific, the list of products concerned) with the details of findings and its impact if any on the benefit-risk profile of the product has to be included in the document.
Regulatory Timeline: The Marketing Authorization Holder (MAH) should submit the renewal application by the recommended submission dates published on the EMA website and, in any case, no later than 9 months before the marketing authorisation ceases to be valid.
Risk Management Plan (RMP)
The main objective of RMP is to document the risk management system considered necessary to identify, characterize, and minimize a medicinal product’s important risks. The three major sections of this document include the following-
Safety specification: It describes the significant information on important identified and important potential risks and missing information and on safety concerns which need to be managed proactively.
Pharmacovigilance Plan: It provides the planning of pharmacovigilance activities to characterize and quantify clinically relevant risks and to identify new adverse reactions.
Risk minimization plan: It includes the planning and implementation of risk minimization measures (RMM), including the evaluation of the effectiveness of RMM activities.
MAH is responsible to maintain a proper risk management system and to monitor continuous influx of safety data from multiple sources for the identification of any new risks and changes to the risk‑benefit balance of the product. In general, RMP is warranted to prepare with the first 5-year renewal and in the time period when the first PSUR following the first 5 year renewal is due for submission, to review the list of safety concerns and the planned and ongoing pharmacovigilance and risk minimization activities.