PSUR - General Principles

PSUR - GENERAL PRINCIPLES

ONE REPORT FOR PRODUCTS CONTAINING ONE ACTIVE SUBSTANCE AUTHORISED TO ONE MARKETING AUTHORISATION HOLDER

Ordinarily, all dosage forms and formulations as well as indications for a given pharmacologically active substance for medicinal products authorised to one marketing authorisation holder (MAH) may be covered in one PSUR. Within the single PSUR, sepa-rate presentations of data for different dosage forms, indications or populations (e.g. children versus adults) may be appropriate.

PRODUCTS AUTHORISED TO MORE THAN ONE MAH

Each MAH is responsible for submitting PSURs, even if different companies market the same product in the same country. When companies are involved in contractual relationships (e.g. licenser–licensee), arrangements for sharing safety information should be clearly set out. To ensure that all relevant data is reported to the regulatory authorities, respective responsibilities for safety reporting should also be clearly specified.

COMBINATION PRODUCTS

For combinations of substances which are also autho-rised individually, safety information for the fixed combination may be reported either in a separate PSUR or included as separate presentations in the report for one of the separate components, depending on the circumstances. Cross-referencing all relevant PSURs is essential.

GENERAL SCOPE OF INFORMATION

All relevant clinical and non-clinical safety data should cover only the period of the report (interval data), with the exception of regulatory status informa-tion on authorisation applications and renewals and data on serious, unlisted ADRs, which should be provided for both the period in question and as cumu-lative summary tabulations starting from the IBD. A listed ADR is one whose nature, severity, specificity and outcome are consistent with the company core safety information (CCSI) (ICH, 1996). A serious ADR is defined as any untoward medical occurrence that at any dose results in death, is life threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or signifi-cant disability/incapacity or is a congenital abnormal-ity/birth defect (ICH, 1994).

The safety information contained within the PSUR comes from a variety of different sources. These include spontaneous reports of adverse events from differ-ent countries, the literature, clinical trials, registries, regulatory ADR databases and important animal find-ings. The main focus of the report should however be ADRs. For spontaneous reports, unless indicated otherwise by the reporting healthcare professional, all adverse experiences should be assumed to be ADRs; for clinical trial and literature cases, only those judged not related to the drug by both the reporter and the manufacturer/sponsor should be excluded.

Reports of lack of efficacy specifically for drugs used in the treatment of life-threatening conditions and for certain other medicinal products, such as contraceptives and vaccines, may represent a significant hazard, and in that sense may be a safety issue. These types of cases should be discussed in the PSUR.

PREPARATION OF PSURS ACCORDING TO THE IBD

Each medicinal product should have as an IBD the date of the first marketing authorisation for the prod-uct granted to any company in any country in the world. For administrative convenience, if desired by the MAH, the IBD can be designated as the last day of the same month. When the CIOMS II propos-als were first incorporated into European regulations, they were modified to include the concept of a Euro-pean birth date rather than an IBD. This effectively implied that PSURs currently scheduled to the IBD had to be rescheduled to the first European approval date – which seemed to run counter to the drive for harmonisation. Fortunately ICH E2C reverted to the IBD for scheduling reports, so now the European birth date is the same as the IBD for medicinal products first authorised in the European Union (EU), and the MAH may use the IBD to determine data-lock points (DLPs) in Europe. The DLP is the date designated as the cut-off for data to be included in a PSUR.

FREQUENCY OF REPORTING

Each PSUR should cover the period since the last update report and should be submitted within 60 days of the last DLP. The need for a report and the frequency of report submission to authorities are subject to local regulatory requirements. The age of a medicinal product on the market may influence this process. Moreover, during the initial years of marketing, a medicinal product will ordinarily receive authorisations at different times in different countries. It is during this early period that harmonisation of reporting is particularly important. Once a product has been marketed for several years, the need for a comprehensive PSUR and the frequency of report-ing may be reviewed, depending on local regulations or requests while maintaining one IBD for all regu-latory authorities. In Europe, for example, the last 6-month PSUR should be provided at the first renewal while for subsequent renewals either a single 5-year PSUR or separate 6-month or yearly PSURs cover-ing 5 years, together with a PSUR bridging summary report, are required.

RESTARTING THE CLOCK

Approvals beyond the initial approval for the active substance may be granted for reasons including new indications, dosage forms, routes of adminis-tration or populations beyond those for which the active substance was initially authorised. The poten-tial consequences for the safety profile of new types and extent of population exposure should be discussed between the regulatory authorities and the MAH because they may influence the require-ments for periodic reporting. When an amendment is proposed to the PSUR submission cycle, the applicant should submit a reasoned request for the amend-ment as part of the application for a marketing authorisation.

REFERENCE SAFETY INFORMATION

The CCSI is derived from the company core data sheet (CCDS), which contains all relevant safety informa-tion, which the company requires to be listed for the drug in all countries where it is marketed. The CCSI forms the basis for determining whether an ADR is listed or unlisted, as opposed to labelled or unla-belled. If the ADR reported is found in the approved product information for a given country, the event is considered labelled. If not, it is unlabelled. The Euro-pean Summary of Product Characteristics (SPC) or locally approved product information continues to be the reference document upon which labelledness (or expectedness) is based for the purpose of local expe-dited post-authorisation safety reporting, so labelled-ness is country-specific. Listedness, by contrast, is uniform across all countries, and it is listedness that must be determined for the PSUR.

DESCRIPTION OF THE REACTION

The reaction terms used in the PSUR will generally be derived from whatever standard terminology (‘controlled vocabulary’ or ‘coding dictionary’) is used by the reporting MAH. In many cases, this will be the Medical Dictionary for Regulatory Activ-ities (MedDRA). MedDRA was developed in the early 1990s under the auspices of the ICH and is an important step towards the standardisation of termi-nology regarding the registering, documenting and safety monitoring of medical products. Its use in spontaneous reporting systems is now a regulatory requirement in some countries, and it is widely used in the preparation of PSURs. In November 1997, the FDA replaced its spontaneous reporting system and its conventional dictionary, the Coding Symbols for a Thesaurus of Adverse Reaction Terms, with the new adverse events reporting system and the MedDRA terminology. MedDRA is also a key part of the electronic database systems used by European and Japanese authorities. MedDRA is not perfect, however, and there are still issues regarding its imple-mentation that need to be resolved. For example, there are important differences in the ways that safety databases interface with the dictionary and uncertainty about the most appropriate way to manage version changes (Brown, 2004).