Safety Reports

Preparation, interpretation & relevance

Safety reports play a key role in the assessment of drug safety. While preparation of these reports is a mammoth task, appropriate approval and authorisation, distribution and monitoring of timely compliance as well as archiving of prepared submissions is inclusive in the process.

Safety Reports are essential documents, which are crucial to the global process of assessment of Drug Safety. Safety Reports are designated as Periodic Safety Update Reports (PSUR), Addendum Reports (AR) and Summary Bridging Reports (SBR), depending on the periodicity of the submissions as well as the contents of the document. The regulatory requirements, in most countries make it obligatory to submit the PSUR for all Registered Products and not merely for Marketed Products. Annual Safety Reports and Development Safety Update Reports (DSURs) cover the Safety Summary from Medicinal Products which are in Development or in Clinical Trials.

A Periodic Safety Update Report (PSUR) is a Safety Report, encompassing complete, global Product Safety Information for a registered product, which is periodically submitted to the regulatory ruthorities, at a defined point in time, Post-Authorisation of the Product.  The periodicity of the submission is determined by the stage of the Product Lifecycle and may change whenever there is any novel safety information or extended Product indication or extended population use for the product.

The Addendum Report (AR)  provides the most recent update to the PSUR. It is usually a safety update outside the usual schedule (upto 6 months since the last PSUR). This document is usually brief, and does not provide any in-depth analysis.

The Summary Bridging Report (SBR) covers a specified period and is prepared on the request of the Competent Authority. This document integrates information presented in two or more PSURs.

Both the AR and the SBR are brief documents which are attached to the PSUR, and hence this discussion will relate primarily to PSURs.

The guidelines that are currently considered for the preparation of this document include the Regulation 726/2004/EC (March 2004) and Directive 2001/83/EC (November 2001) and the Volume 9A (September 2008) which correlates most closely with the ICH E2C guidelines.

Expectations of the authorities

The Competent Authority requires that the Safety Report received from the Marketing Authorisation Holder (MAH), provides a complete validated summary of Product Safety in the Development Phase and the Market Lifecycle of the Product. It is expected that this document will be the source of comprehensive Pharmacovigilance data which is available within the company and made available to the Authority for a review of the product. In the Safety Report, the MAH is expected to review the safety profile, assess the Risk-Benefit Balance of the Product, and update the Summary of Product Characteristics (SmPC) and the Package Leaflet based on currently available safety Information.

Goals of safety reports

For most EU authorities, the acceptable format is as defined in Chapter 1.6 of the Volume 9A document. The focus of the document for the MAH should be the presentation, analysis and evaluation of new or changing safety data received in the period covered by the document. The Safety Summary is expected to provide a critical evaluation of Product “Risk-Benefit” in the light of dynamic safety knowledge.

Submission cycle

Safety Report submission is mandatory for all products following  registration. While submission cycles vary slightly from region to region, the usual cycle which is followed in the countries of the European Union is 6 monthly for the first two years after registration annually for the next 2 years and at 3 yearly intervals thereafter.

The international birth date – that is, the date of first marketing authorisation granted to any MAH anywhere in the world – is the date that is conformed for the Data Lock Point (DLP). Submission of the report to the competent authority is required within 60 days of the DLP; rarely the submission date is extendible by 30 more days on prior request. Some national authorities do require that the PSUR submission cycle follows the national birth date, that is, the date of first marketing authorisation in the country. In these cases, providing an addendum report to the most recent PSUR is usually satisfactory.

For renewal of marketing authorisation after 5 years of marketing, reports are prepared covering a period of at least 4 years and 4 months. These reports are submitted within 60 days after DLP. As a rule, the renewal of marketing authorisation does not change the original reporting schedule of the product. The periodicity of the safety report, may change with line extensions. It also changes with the authorisation of generic products and may be shorter for products with a risk management plan in place that require special monitoring.

Process engineering

The decision on preparation of the PSUR is determined by the periodicity of the Product as well as the marketing life cycle of the product. The planning and preparation is resolved in keeping with the Submission timelines and based on the international birth date or the national birth date as per the requirements of the competent authority in question and commenced before the data lock point. In cases where the marketing of the product is authorised to more than one MAH, it is expedient to qualify the data source in order to avoid data duplication, which may sometimes be a concern.

While the preparation of the document is in itself a mammoth task, appropriate approval and authorisation of the prepared PSURs, distribution and monitoring of timely distribution compliance as well as archiving of prepared submissions is inclusive in the process. An easy aid to this process is a timetable of expected submissions based on the data lock point of the product.

The PSUR must cover the following

  • All Indications
  • All Dosage forms
  • All Regimens of Treatment
  • Separate PSURs required for Fixed Combination Products
  • Address comments of the Competent Authority on previous PSURs
  • Use English language (in most countries)

Executive summary

This section is a composite of the different sections that are presented in the later sections. It provides an overall impression of the safety profile of the product. This review would include the worldwide MAH status of the product and other relevant regulatory information.  It would summate the information from spontaneous cases, studies, and literature. The summary would provide data on exposure of the product and discuss new signals and safety concerns, if any. Usually, the executive summary would be written at the conclusion of all sections of the PSUR, to enable the author to provide a synopsis of  past, current and future safety related information of the product.

Regulatory safety information

Sections 3 & 4 of the PSUR, which provide regulatory related safety information, include notification on global regulatory status of the product, including any qualifications, limits to indication, product withdrawal and restrictions to treatment populations. Any updates from the regulatory authority or any company actions related to safety, including differences in previous and current information, target use populations, urgent safety restrictions, Dear Dr letters, for the product, would be presented in this section.

Reference safety information (RSI)

In practice, the company core safety information (CCSI) is used for RSI purposes. The concerned document should be numbered, dated and appended to the PSUR. The RSI/ CCSI should be used to assess listedness, and the local / EU Summary of Product Characteristics (SPC) to define expectedness. For 6six-monthly and yearly PSURs, the RSI coming into effect at the beginning of the reference period is used. For PSURs covering a period greater than one year, the latest effective RSI is used. Details and evidence for changes to CCSI during the reference period are provided, within the PSUR document.

Patient exposure data

The world wide sales data is used to estimate Patient exposure. An average daily dose assumption is made, and patient exposure is provided in terms of person-time-exposure (days, months, years). It is expected that details on method of estimation of patient exposure is provided. In case it is relevant to the safety assessment, broken down patient exposure data can also be provided in terms of market versus clinical exposure, adult vs paediatric or geriatric exposure.

A satisfactory case description is one in which patient and reporter demographic information and description of ADR, progress and outcomes; company causality, dechallenge and rechallenge information is made available. All unsolicited cases regardless of causality are included in the assessment. In addition, serious solicited cases that are assessed as ‘Suspect’ are also included. The cases which are selected for analysis are those with relevant safety findings rather than the rare cases. In cases with serious, unanticipated findings, comments are provided.

The Line listings provide a short summary of all the cases discussed in the PSUR. The Tabulations provide specific details on certain groups of patients. The purpose of Case Analysis, Line listings and Tabulations is to create ‘Medically Meaningful Clusters’ – which allows proper assessment of the safety information. Meaningful interpretations can also be drawn from the background information, reporter frequency as well as quality of reports.

Additionally, for the specified period, the published scientific literature is reviewed for all the safety related information. In instances where relevant cases are found within literature, these are provided in the case listing.

Studies

Product studies included within the PSUR are non-clinical, clinical, and epidemiological studies. A description of the studies is provided, along with a discussion on the safety sample and the safety relevance of studies. The basis for any new, planned safety studies is as well discussed. Meanwhile, published studies are discussed in the light of their safety relevance.
Other information in the form of efficacy related information, late breaking information and follow-up of cases of special interest from previous PSURs is also made available in this section.

Safety-related information

In this section, follow-up of risk management plans and a risk-benefit analysis of the product is provided.

Safety evaluation

Statistical ratios such as the proportional reporting rate are used to assess new, serious or increased ADR rates. The identified Safety signals are discussed and measures proposed – heightened surveillance, change to the reference safety information, routine monitoring, or no action.
The overall safety evaluation also includes a discussion on any new or increased drug interactions, overdose, misuse / abuse, and use in pregnancy / lactation, or in special patient groups – such as paediatric or geriatric population.

Conclusion

Any variation of data in comparison to the previous experience or disparities from the reference safety information document is discussed in this section. All safety actions taken are listed and justified. In case there are amendments to Summary of Product Characteristics (SPC), these are discussed. The conclusion section should clearly delineate the risk-benefit balance for the product.

Peer review

The safety reports require to be peer reviewed by medical affairs, product department, clinical and regulatory affairs for correctness and validation of different parts of the document. For the European authorities, the PSUR is prepared by the product safety expert and authorised by the qualified person.

Archiving

The signed paper copies and peer reviewed copies are archived at the central office, where the documents originate. In the different affiliates, the submission documents as well as the covering letter will require to be archived. The distribution list also forms part of the archives. All correspondence with the competent authorities, is archived for future reference as well as for audit / inspection purposes.

Consonance in pre and post-marketed Phase

The Annual Safety Report or the DSUR for products in development phase will transition to the PSUR document in the phase of product registration and thereafter. Pharmacovigilance risk management plans from the clinical phase can be switched to the post-marketing phase as per product safety requirements and regulations.

What is deemed as non-compliance with safety report regulations?

Complete non-submission or submission outside the stipulated timeframes is the most common form of non-compliance. Besides, submission in the incorrect format, poor quality of reports, and omission of key information, are other forms of non-compliance. Failure to address the comments or requests from the Competent Authority to the previous PSUR is also considered as non-compliance.

Amendment to periodicity of PSURs

The following situations could change the periodic cycle of PSUR submission – line extensions, pediatric indications, new indications or use in new populations, dosages, routes of administration. One possible reason for the change in the periodic cycle of the PSUR could be specific safety concerns which necessitate the provision of risk management plans.

List of appendices

  • Worldwide MAH Status
  • CCSI
  • Serious and non-serious unlisted ICSRs/ADRs from Health Care Professional
  • Non-serious listed ICSRs/ADRs from Health Care Professional
  • ICSRs/ADRs from consumers
  • Serious ADRs, all-time
  • Listing of studies
  • Identified or updated safety signals
  • Risk benefit analysis report
  • Bibliography

Safety Report Requirements by Various Authorities

US FDA

The US FDA Safety Report has four sections fulfilling usually the same objectives as the EU PSUR. It is acceptable to these authorities to submit on basis of international birth date rather than on national birth date. The submission cycle is quarterly for the first three years of registration and annually thereafter. The document has four sections which capture the same data as per the Volume 9A requirements for PSURs.

Health Canada

PSURs are not routinely submitted to the Canadian authorities, Health Canada. They are habitually required to be submitted within 30 days and on request only. Sometimes PSURs may be requested annually or biannually depending on the product safety characteristics. The CCSI and Local labeling  comparison document is provided along with the PSUR.

PSURs are also submitted along with Regulatory submissions which involve local labeling safety updates.  The PSUR format prepared for submission per Vol 9A is usually acceptable to the Health Canada authorities.

TGA, Australia

PSURs (and ARs and SBRs if relevant) are submitted annually to cover a period of three years from the date of local registration. The first PSUR must be submitted no later than 15 months after approval and subsequent reports are submitted annually. The format of the documents as described in the ICH guidelines or the Vol 9A are acceptable to the TGA authorities. TGA does not specify precise requirements and IBD is acceptable provided it meets the submission timelines as noted above.

Wrap up

The PSUR and related Safety Reports are the presentation of comprehensive safety evaluation available from all sources for the period under discussion. This document aims to address relevant, current safety issues and provide resolution for those safety concerns that continue to exist.

The current move to define the Development Safety Update Reports and the Annual Safety Reports will ensure alignment of product safety during the pre-marketed and post-marketed phases of the product life-cycle, and may likely prevent or at the very least reduce the occasions of Product withdrawal due to safety related concerns.

The key imperative seems to be the analysis and inferences to be drawn from the data, rather than a mere presentation of data in the standard format. A good document serves as a guide to comprehend the product safety profile and provide recommendations, if any, on further required safety actions. The intent of the actions should be to ensure complete knowledge on product safety and thus to proactively guarantee patient safety.

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