What format and submission obligations a periodic report answers to
A periodic safety report is written to a defined format, submitted at defined points and assessed on a defined route. The format rests on ICH guidelines, and each region adds obligations of its own: the European Union its legislation, its reference dates, its central repository and its single assessment of reports on one active substance, the United States its own periodic report, and China its own language, content and timing requirements.
ICH periodic reporting standards
ICH E2C is a common standard for periodic benefit-risk evaluation reporting on approved medicinal products, including those under further clinical development, within the ICH regions. Its current, revised version, E2C(R2), was finalised in November 2012. Regulators believe that the E2C(R2) format meets the national and regional requirements for periodic safety reporting. ICH E2F, the guideline on the development safety update report (DSUR), is the corresponding common standard for periodic reporting on drugs under development, including marketed drugs under further investigation, among the ICH regions, and its current version was finalised in August 2010.
The periodic benefit-risk evaluation report (PBRER) replaced the periodic safety update report (PSUR), which was itself an attempt by ICH to harmonise the format for safety reporting and which focused, as its name implies, on drug safety. But there was increasing recognition that the safety of a product should be interpreted in the context of its benefit: the threshold for acceptable safety risks is higher in an oncology product than in a cough mixture. The PBRER, as its name implies, attempts to put safety issues into that context. During drug development the number of patients exposed to a drug may be too small to detect small but important safety signals reliably, and the populations are often limited to ideal ones. Once the drug is on the market, many more patients are exposed, including patients who would not have been included in clinical trials, and these real-world data give important additional information on its use in clinical practice.
The PBRER's main objective is a comprehensive, concise and critical analysis of new or emerging information on the risks of the medicinal product and on its benefit in approved indications, enabling an appraisal of the product's overall benefit-risk profile in the context of the cumulatively available information. Its benefit-risk section is in many ways similar to the benefit-risk sections of a clinical overview. Like the DSUR, the PBRER is not intended to provide initial notifications of significant new safety information, and it is not a means by which new safety concerns are detected.
The PSUR format and its legal basis in the EU
In the EU, the objectives and format of the PSUR are laid out in Good Pharmacovigilance Practices (GVP) Module VII. The required format and content of the PSUR in the EU are based on those of the PBRER described in ICH E2C(R2), and the format replaces the one previously described in E2C(R1). To keep the terminology consistent with the one used in the EU, the PBRER format is still called the PSUR there, and the two names denote the same document. The format changed so extensively that marketing authorisation holders made significant changes to their production, review and assessment processes. The legal requirements for submission of PSURs are established in Regulation (EC) No 726/2004, Directive 2001/83/EC and Commission Implementing Regulation (EU) No 520/2012 on the performance of pharmacovigilance activities.
What the PSUR is for
A PSUR evaluates a product after authorisation, and marketing authorisation holders must submit PSURs at defined time points following a medicine's authorisation. The PSUR, the US periodic adverse drug experience report (PADER) and the documents associated with them, the PSUR addendum and the summary bridging report, must be submitted at periodic intervals after marketing authorisation. They are meant to let the marketing authorisation holder keep reviewing the product's safety profile and keep the regulating authorities updated on it, so that any changes and potential risks can be quickly identified and addressed. PSURs give marketing authorisation holders an opportunity to review the safety profile of their products and ensure that the summary of product characteristics and the package leaflets are up to date. A PSUR evaluates the benefit-risk balance of a medicine as evidence is gathered in clinical use, in everyday practice and with regard to long-term use.
A PSUR aims to evaluate thoroughly and critically any information on risks, safety concerns and signals, and also any new information on benefit. Benefit can evolve during the lifecycle too, since new evidence from studies, or from the post-marketing setting itself, may show a higher or a lower benefit. So the benefit-risk profile may evolve over the lifecycle, and the PSUR is the post-marketing tool for regularly re-evaluating and reassessing it.
The European Medicines Agency (EMA) uses the information in PSURs to determine whether new risks have been identified for a medicine or whether the balance of its benefits and risks has changed. On that basis, the agency decides whether further investigations need to be carried out or whether action has to be taken to protect the public from the risks identified, for example by updating the information provided for healthcare professionals and patients.
Content of the PSUR
The full E2C(R2) guideline specifies the required format, including the table of contents and section numbering, and Section 3 of the guideline gives specific guidance on content. A PSUR includes a summary of the benefits and risks, new or emerging information on benefits and risks, and the results of all studies of both authorised and unauthorised uses, and cumulative data from previous reports are incorporated in the benefit-risk evaluation. The PSUR gained the evaluation of benefit with the E2C(R2) format, and unless the safety or benefit-risk profile has changed during the reporting period, a concise discussion of benefit is usually sufficient. For efficacy and effectiveness, the report must contain the evaluation of the medicine from the International Birth Date, include relevant new safety information and cumulative knowledge, and focus on new information. The PSUR covers larger and more diverse populations than pre-authorisation documentation, and its required cumulative analysis and benefit-risk evaluation demand a larger amount of data.
A single PBRER is prepared on all approved indications, dosage forms and regimens for the active substance. Separate PBRERs may be acceptable in exceptional cases and upon agreement with the regulatory authorities, such as an active substance used in two formulations for systemic and topical administration in entirely different indications, or fixed-dose combination products marketed separately.
How often the PSUR falls due
The PSUR is a post-marketing periodic report whose frequency is risk-proportional and set in the terms of the marketing authorisation. Under GVP Module VII it is usually due every six months during the first two years after the product is first placed on the market, then annually for the following two years, and every three years thereafter, unless the health authority requires otherwise.
The PSUR repository
As of 13 June 2016, all PSURs for human medicines authorised in the EU must be submitted to the PSUR repository, which the agency developed in close collaboration with the EU member states and industry. The repository is a single, central platform for PSURs and related documents, to be used by all regulatory authorities and pharmaceutical companies in the EU, and it was introduced by the EU pharmacovigilance legislation to facilitate the exchange of information on the safety of authorised medicines between regulators and companies. From that date, marketing authorisation holders must use the repository as the single point for all submissions and should no longer submit their PSURs to national competent authorities. The eSubmission Gateway is available on the eSubmission website.
The repository simplifies submission for marketing authorisation holders by letting them send all PSURs to a single recipient, and it facilitates assessment by ensuring that national competent authorities, the agency and its scientific committees have timely and secure access to all relevant documents. The repository was first released in January 2015, and in June 2015 the agency's Management Board gave the green light for its use following an independent audit that confirmed it met the agreed functional specifications. Since the initial release, the agency has supported companies and national competent authorities in getting ready to use the repository. The system was implemented in phases, with feedback from users taken into account to improve it, and guidance, interactive training sessions and links to all relevant documents were made available on the agency's eSubmission website.
EU single assessment of PSURs
In the EU, the periodicity and data lock points of PSURs are defined in the legally binding European Union reference dates (EURD) list, and the alignment of periodicity ensures parallel assessment of the PSURs of all products containing the same active substance. The PSURs of medicinal products that contain the same active substance or the same combination of active substances are jointly assessed in a single assessment procedure. The single assessment of nationally authorised medicines is a deliverable of the 2010 pharmacovigilance legislation, and it aims to harmonise and strengthen the review of the benefits and risks of all medicines across the EU. Single-assessment procedures involving a combination of centrally and nationally authorised medicines have been in place since April 2013. Before 2015, PSURs for medicines containing the same active substance or the same combination were submitted by their respective marketing authorisation holders to different national competent authorities at different times. Since 2015, the agency has carried out single assessments of PSURs for nationally authorised medicines containing the same active substances or combinations.
The introduction of single assessment helped to streamline the process and to ensure that all the evidence generated about medicines containing the same active substance is reviewed at the same time by one authority, resulting in consistent safety information. The joint assessment also helps to optimise the use of resources between national competent authorities. Single assessments of PSURs are a key post-marketing regulatory tool to ensure that patients receive up-to-date information on the safety of medicines, and PSURs provide regular opportunities for monitoring medicines in a public health space that, in 2017, covered nearly 500 million people.
The PSURs are assessed by the agency's Pharmacovigilance Risk Assessment Committee (PRAC) together with a leading assessor from one nominated national authority, the lead member state. The procedural guidance of September 2014 assigned the assessment either to a PRAC member, for procedures involving a combination of centrally authorised medicines and medicines authorised through mutual-recognition, decentralised or purely national procedures, or to a member state appointed by the Coordination Group for Mutual Recognition and Decentralised Procedures – Human, for procedures involving nationally authorised medicines only. Every EU single assessment results in a recommendation from the PRAC. The procedure produces one single-assessment report, which is shared among the marketing authorisation holders whose products are part of it. The holders may comment on the report, and the PRAC then adopts its recommendation. The recommendations made during the assessment are legally binding, applicable to all member states and implemented across the EU.
Under the procedural guidance of September 2014, holders of medicines subject to a single assessment involving nationally authorised medicines only, for which the frequency and dates of submission are established in the EURD list, had to submit their PSURs to the agency and to all member states where the medicine was authorised. This applied to medicines with data lock points on or after 1 September 2014. For all single-assessment procedures starting from October 2014, the procedure number was to be published in advance in the EURD list, so holders were to include it when preparing their submission. Holders of nationally authorised products were also to complete Annex I of the formatted table template of the cover letter. The PSUR timetable was adapted to integrate the single-assessment procedures containing nationally authorised products, and the adapted timetable was published in July 2014. Under that guidance, the PSURs of nationally authorised medicines containing substances or combinations with no single-assessment procedure established in the EURD list remained assessed at national level. As of 26 August 2014, marketing authorisation holders have to pay a fee for the assessment of PSURs.
In April 2017, after two years of experience with the single assessment of PSURs for nationally authorised medicines, the agency issued two documents as part of its commitment to continuous process improvement: an Explanatory note to GVP Module VII and an Assessors' questions and answers guidance on PSUR single assessment. Both aim to improve the safety information and benefit-risk assessment of medicines in the context of the single assessment.
The US periodic adverse drug experience report
A PADER is an aggregate safety report that a sponsor or marketing authorisation holder is required to submit to the US Food and Drug Administration (FDA) after obtaining marketing approval. Submission therefore starts after phase 3 trials are completed and the FDA approves a new drug application for an innovator product, an abbreviated new drug application for a generic product or a biologics licence application for a biological product. A PADER summarises the adverse event data of the reporting period and typically includes a narrative summary, line listings of individual case safety reports and the current US package insert, and it follows a US-specific format that is generally more concise than the globally harmonised PBRER. Although the FDA recommends periodic submission of a PADER under 21 CFR 314.80, a marketing authorisation holder can submit the PSUR/PBRER with new drug application listings, also called the US supplement or FDA PSUR, in place of a PADER after obtaining a waiver under 314.90(b) and 600.90(b).
One comparison of the two reports sets out their important differences.
| Aspect | PADER | PBRER |
|---|---|---|
| Content focus | Individual case narratives for fatal outcomes and events of special interest | Detailed benefit-risk analysis of the medicinal product |
| Regulatory guidance | Prepared under 21 CFR 314.80; submitted to the FDA | Prepared under ICH E2C(R2) and GVP Module VII; submitted to the EMA and other regulators |
| Structure | About five sections; relatively less complex | About twenty sections; a more complex document |
| Includes | Serious unlisted events, regulatory updates | Regulatory updates, exposure data, clinical trials, signal overviews, benefit-risk assessment |
| Product scope | A separate PADER for each new drug application; formulations can be combined with justification | Usually one PBRER per product; different indications and formulations can be separated with justification |
| Submission frequency | Quarterly for the first three years after approval, then annually | Every six months for two years after approval, then annually |
| Submission timeline after the data lock point | Quarterly: within 30 days; annually: within 60 days | Annually or multiyear: within 70 or 90 days |
The comparison gives the PBRER as annual after its first two years, while the schedule under GVP Module VII turns to every three years after the first four.
Periodic reports in other regions
As of 2012, the pharmacovigilance requirements of Japan, Canada, Australia, New Zealand, India, Singapore and Taiwan generally followed the ICH guidance, format and standards.
The PSUR guidelines of China's regulator, the SFDA, in the version dated 6 September 2012, were mainly based on ICH E2C. They differed from it mainly in three ways: every part except the line listings and the summary tabulations had to be submitted in Chinese or with a Chinese copy; any differences in China's situation from other countries, such as drug indications, formulations and dosages, and any safety information, had to be addressed and explained; and updates were required once every year in the new-drug monitoring period of three to five years and every five years thereafter. As of 2013, no periodic safety reports were required in China for non-marketed products.