Periodic Safety Update Report


Nidhi Saxena Xcellon Institute


Document that allows a periodic, comprehensive assessment of the worldwide safety data of a marketed drug or biological product. Concept evolved from the CIOMS Working Group II report in 1992.

Formed the basis for ICH-E2C guidance for the industry
− − −

Defined the format and content for PSURs Introduced the concept of an international birth date Set the period for review of interval safety data as 6 months.


To evaluate to show whether a product's safety profile has remained the same of has undergone changes Changes should be made to product information to optimise the use of a product Rare adverse drug reactions can be easily identified As the drug become available for indefinite use, delayed onset ADRs become easier to identify.

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PSUR- General Principles

One report for the products containing one active substances authorized to one marketing authorization holder (MAH)

PSUR should cover all dosage forms, formulation and indication Separate presentation of data for different dosage forms or populations if appropriate 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 arrangements for sharing safety information should be clearly set out.

Products authorized to more than one MAH

General Principles-Cont....

Combination Products

Safety information may be done as a separate PSUR or included as separate presentations in the report for one of the separate components with cross-referencing.

General Scope of information:

The report should present data for the interval of the PSUR only except for regulatory status information, renewals and serious unlisted ADRs, which should be cumulative. Report should focus on ADRs. All spontaneous reports should be assumed be reactions. Reports should be from health care professionals. Lack of efficacy reports should not be included in the tables but should be discussed in the “other information” section.

 

Preparation of PSURs According to the IBD
• International Birth Date (IBD)
– Date of the first marketing authorization for the product granted to any company in any country in the world. Each medicinal product should have IBD This date should be synchronized around the world for PSUR reporting such that all authorities receive reports every 6 months or multiple of six months based on IBD.

– –

Frequency of Reporting
• • • PSUR should cover the period since the last update report submitted within 60 days of the last DLP (data lock Points) Need and frequency of the report submission to the authorities are subject to local regulatory requirement. Age of a medicinal product on the market may influence the process. product marketed for several years, need comprehensive PSUR and frequency of reporting may be reviewed depending upon local regulation.

• •

Restarting the Clock
• Approvals beyond the initial approval for the active substance may be granted for reasons including
– – – – new indication Dosage forms Routes of administration Populations beyond those for which the active substance was initially authorized.

Safety profile of new types and extent of population exposure may influence the requirement for periodic reporting, necessitating discussion between regulatory authorities and MAH Proposed amendment to the PSUR submission cycle should be submitted with reasoned request along with application for marketing authorization.

Reference Safety Information
• Company Core Safety information(CCSI) – – derived from Company core data sheet (CCDS) Contains all relevant safety information required by the company to be listed for the drug in all countries where it is marketed

• •

CCSI will determine whether an ADR is listed or unlisted, as opposed to labelled or unlabelled. Labelledness is country specific whereas listedness is uniform across all the countries and therefore it must be determined for the PSUR. – labelledness is based on SmPC Summary of Product Characteristic for the purpose of local expedited post authorization safety reporting.

Description of the reaction
• Verbatim reporter term as well as standardized coding term (i.e MedDRA,which was approved after E2C was finished) should be used. FDA replaced its spontaneous reporting system and its conventional dictionary, the Coding Symbols for a Thesaurus of Adverse Reaction Terms, with new adverse events reporting system and the MedDRA terminology MedDRA is important part of the electronic database system used by European and Japanese authorities.

Regulatory Requirements
• ICH E2C is followed in all three ICH regions, however the reporting requirements differ in these region:

EU,Council Directive/93/39/EEC and Council Regulation
• Report should be submitted every 6 months for first 2 years, annually for next three years and then five yearly after the first renewal

USFDA-quarterly reports during first 3 years, then
annual reports

Japan-survey on cohort of a few thousand pts.

Established by a certain number of identified institutions during 6 years following authorization. Adverse reactions which are non-serious, but both mild in severity & unlabelled, must be reported 6 monthly for 3 years and annually thereafter.

Section number

Content of PSUR Section
Executive Summary Introduction Worldwide Market Authorization Update on regulatory authority or market authorization holder action taken for safety reasons Changes in reference safety information Patient exposure Presentation of individual case histories Studies Other information Overall safety evaluation Conclusion Company Core Data Sheet Marketing Authorization status Line listing of Case Report Summary tabulations of events

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 Appendix 1 Appendix 2 Appendix 3 Appendix 4

PSUR content
• Title
– Statement of confidentiality of the data and conclusions included in the report Brief overview providing the reader with a description of the most important information Sets the scene and puts the report in context Cross referencing it to previous reports Describing products/formulation that are included and excluded Pharmacology of the product Indications and co-licensing agreements

Executive Summary

– – – – –

Worldwide Marketing Authorization Status
– A table with dates of market authorization and renewals, indications, lack of approvals, withdrawals, date of launch and trade names

PSUR Contents Cont...

Update on Regulatory Authority or MAH Actions taken for Safety Reasons:
– – – – – – – Marketing authorization, withdrawal or suspension Failure to obtain a marketing authorization renewal Restriction on distribution Clinical trial suspension' Dosage modification/ formulation changes Changes in target population or indications It should discuss the safety related reasons that led to the actions described & append the appropriate documentation.

PSUR Content Cont...
• Changes in Reference Safety Information
– – – – Change in the CCSI The CCDS, which incorporates the CCSI, should be included as an appendix If no CCDS is available, a national SPC can be used. If there is a time lag between changes to the CCDS and local labeling, this should be commented on when submitting to that local health authority. Both market exposure and clinical trials. Estimates rely on gross approx. of in-house or purchased sales data or volume. This includes patient exposed, patient-days, number of prescriptions and tonnage sold.

Patient Exposure
– – –

PSUR content cont.... Presentation of Individual Case Histories
• • • • • Follow up data on previously reported cases Literature should be monitored and cases included. Duplicate should be avoided. If a case is mentioned in the literature, even if obtained also as a spontaneous or trial case, the citation should be noted If medically unconfirmed cases received from consumers should be submitted as addenda line listing and summary reports Line listing should include each pt. Only once. If a patient has more than one ADR, the case should be listed under the most serious adverse drug experience with the others also mentioned there. More than one listing for different dosage forms and indication is advisable

PSUR Content cont... Presentation of Individual Case Histories
• The headings for the listings are:
– – – – – – – – – – MAH reference number Country where the case occurred Source (trial, literature,spontaneous, regulatory authority) Age and Sex Daily dose, dosage form and route of suspected drug Reaction onset date Treatment dates Description of the reaction (MedDRA code) Patient outcome at the case level (resolved) Comments

PSUR Content Cont.... Presentation of Individual Case Histories
• Line listing should include the following causes:
– – – – – Spontaneous reports: all serious reactions, nonserious unlisted reaction Studies or compassionate use Literature:all serious and non-serious reaction Regulatory authority cases: all serious reactions If nonserious, listed ADRs are required by some authorities, they should be reported as an addendum Data in summary tabulation should be noncumulative except for ADRs, which are both serious and unlisted for which cumulative figure should be provided in the table

Summary tabulation


PSUR Content Cont....

Refers to only those company-sponsored studies and published safety studies, including:
• Epidemiology studies
– – Producing findings with potential impact on product safety information. Should be included along with a discussion of any final or interim results.

The MAH should not routinely catalog or describe all the studies.

Other Information
– – – May include risk management programmes led by MAH and/or a benefit-risk analysis report Lack of efficacy information should be presented here Late-breaking information after database lock

PSUR Content Cont.... Overall Safety evaluation
Should highlight new information on serious and nonserious unlisted ADRs.  The data should be presented by system organ class and should discuss:

A change in characteristics of listed reaction' Serious unlisted reactions, placing into perspective the cumulative reports Nonserious unlisted reactions Increased frequency of listed reaction New Safety issues

• • • • • •

Drug Interactions Overdose and its treatment Drug misuse or abuse Pregnancy and lactation information Experience in special patient groups Effects of long-term treatment

• • •

PSUR Content Cont....
• Conclusion
– Should indicate safety data which are not in accordance with previous experience and with company CCSI Any action recommended or initiated Company Core Data Sheet (CCDS)


Summary Bridging Reports
• Integrates two or more PSURs that is submitted to regulatory authority to cover a specific time period for which a single report is required. It should not contain new data or repeat the information already included in the PSURs but should cross reference those other reports. format/outline should be identical to the format of the usual PSUR but the content should consist of summary highlights. It should not contain line listing but may have summary tables.

Addendum Reports
• • It is used when it is not possible to synchronize PSURs for all authorities requiring submissions It is an update to the most recently completed and scheduled PSUR that is produced when regualtor requires a safety update outside the usual reporting cycle,and more than a brief amount of time has elapsed since the DLP of the most recent PSUR. It should contain: – – – – Introduction Any changes to the CCSI Significant regulatory actions on safety Line listing and/or summary tabulations and a conclusion.

The PSUR Process
• Comprises of the following steps:
– – – – – Intake of ADR information Case processing Data retrieval Data analysis Medical review and risk assessment

After reporting of ADR, the case is entered into a safety database, a narrative is prepared and a MedDRA term is assigned to ADRs

PSUR Process
• • Can be illustrated by the standard operating procedure (SOP) of H.Lundbeck A/S. There are five stages to Lundbeck's procedure: – – – – – Data collection PSUR writing Approval Archiving distribution

– – – – – – Source for the identification of new safety signals A means for determining changes in the benefit-risk profile Effective means of risk communication to regulatory authorities Indicator for the need for risk management Provide opportunity to review aggregate data Gives chance to detect potential problem as pt. Exposure increases in response to promotional efforts Tool for monitoring the unpromoted use of drug in subpopulation (children, elderly patient etc.)

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