The periodic reporting of aggregate safety reports to regulatory health authorities includes a comprehensive overview of the benefit-risk profile of medicinal product based on cumulative data gathered by Marketing Authorization Holder (MAH) . Since an analysis of benefit-risk profile of a medicinal product is not possible at individual case level, a periodic review of aggregated data becomes critical in analysing the overall benefit-risk balance of a product. These aggregate reports provide an assurance to the regulators that the MAH is continuously monitoring and critically assessing the benefit-risk profile of the product. 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 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.
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 experience. The sources of safety data include Non-clinical studies, clinical studies and Non interventional studies, literature articles, spontaneous reporting system, customer complaints, medical information queries, digital media etc.
The following types of reports are submitted for medicinal products post marketing authorisation.
Marketing authorisation holders are obliged to periodically report the evolving safety profile of investigational medicinal product and actions taken or proposed to address any safety concerns identified during the development, to the respective health authority and other interested bodies (e.g., Institutional review board and local ethics committee).
DSURs are written annually and should be submitted no later than 60 calendar days from the data lock point (DLP).
The date of first authorisation for conducting a clinical trial in any country worldwide is called as developmental International birth date (DIBD) which is the start date of first DSUR of a product. The DLP of a DSUR is the cut-off date for including the data in a DSUR which is the last day of one year period for a DSUR.
In addition to the innovator molecules, DSURs are submitted for the marketed products also, which remain in clinical development even after initial marketing authorization.
The primary focus of DSURs is to provide the safety information from interventional clinical trials followed by observational or epidemiological studies, non-clinical studies and studies published in literature.
The international standard for DSURs follow reporting guidelines set by the ICH under E2F.
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 since last submitted PADER.
The Submission of a PADER starts following completion of Phase 3 clinical trials and with approval of a new drug application ([NDA] for innovator products), abbreviated NDA ([ANDA] for generic products), and biologic license application ([BLA] for biological products) by the US FDA. Hence, for each NDA/ANDA/BLA (for different indication and/or formulation), MAH should submit a separate PADER.
The frequency of PADERs depend on the age of the medicinal product in market. Refer to the table below for the frequency and regulatory timelines for submission of PADERs to US FDA authority.
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
Timeline for PADER submissions
There are some scenarios where the MAH can submit PBRER in place of US PADER to fulfil post marketing safety reporting requirements. This substitute can be applicable in case the MAH has an approved waiver in place to substitute the PBRER/PSUR with PADER.
The submission of PADER follows guidelines of code of federal regulations, 21CFR314.80.
The Benefit-risk evaluation should be carried out throughout the lifecycle 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.
A PSUR/PBRER is the most widely used document to present a comprehensive, concise and critical analysis of the risk-benefit balance of the medicinal product taking into account new or emerging information in the context of cumulative information on risks and benefit.
International birth date (IBD):
The date when a sponsor receives authorisation for marketing a drug in any country of the world, is considered as International birth date (IBD) of that medicinal product.
The Data lock point of a PSUR/PBRER is the cut-off date for the data to be included in the PSUR/PBRER.. PBRER is a complex report with 20 sections including appendices unlike PADER which is comparatively smaller and less complex report. The frequency of the PBRERs varies based on the age of medicinal product in the market. Refer to the table below for the reporting periods and their respective regulatory timelines.
Reporting Interval category
Criteria for medicinal products
Regulatory timeline
6-month
Newly approved and for 2-years following initial marketing authorization
70 calendar days
Annual
For next 2 years
70 calendar days
3 years or more (follows risk-based approach, defined by the regulators)
Thereafter i.e., after 4 years of marketing authorization
90 calendar days
Regulatory timeline for PBRER/PSUR
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 PSUR/PBRERs and related DLPs could be obtained from the European Union reference dates (EURD) list. European Medicines Agency (EMA) updates the EURD list on monthly basis.
PBRERs are accepted by most of the country regulatory bodies for providing the periodic benefit-profile of the medicinal product. Also, most of the countries have now started following the EURD list for the frequency of these periodic reports. However, there are some countries which still do not follow the PBRER frequencies of EURD list. Those countries have their own schedule of PBRERs which needs to be followed by the MAHs having marketing authorization in those countries.
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.
The international standard for PSUR/PBRER follow reporting guidelines set by the ICH under E2C(R2) and GVP Module VII.
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/post-marketing data. The structure and specifications of the ACO and PBRER are somewhat similar. But the information in ACO is presented with greater emphasis on the data received since the last renewal/approval rather than discussing cumulatively. ACOs are considered as renewal documents particularly in EU; however, some other countries of the world also use ACO as their renewal document.
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. Any new signal assessment and new potential or identified risks raised during the renewal period that have not been subject to previous assessment (e.g., in PSURs) should be clearly highlighted in the data provided.
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. The ACO should be submitted within 90 calendar days from the DLP (cut-off date for the data to be included in the ACO).
