5.1 Introduction

Once a medicinal product has been approved for marketing, the marketing authorization holder (MAH) has an obligation to periodically submit a number of pharmacovigilance reports to relevant regulatory authorities in the regions where the product is marketed. These periodic reports are a concise analysis of new safety data gathered since marketing approval, and allow for the continued surveillance of the product’s safety, as well as continued appraisal of potential new risks and changes to the product’s benefit-risk profile, all of which act to ensure the public’s safety.

In this context, it is important to appreciate that safety is not an absolute concept, and medicinal products that have successfully passed through the long drug development process still need to be monitored once they have gained entry to the marketplace. This is due to the nature of the clinical trials conducted during the drug development process, which, for reasons of practicality, generally involve a limited number of carefully selected (and carefully monitored) participants and run for limited durations of time. The consequence of these practical constraints is that, although certain types of side effects are detected during clinical development, others only ever come to light once the product is in the marketplace, being used by a much larger patient population outside the confines of the tightly controlled and regulated clinical trial environment. Viewed in this light, the need and importance of continued surveillance facilitated by the effort that informs the preparation of the periodic and mandated post-marketing pharmacovigilance documents is inarguable.

As such, these post-marketing pharmacovigilance documents allow both the MAH and the regulatory authority periodic and continued reviews of the product’s safety profile by presenting:

• a summary of any changes in the product’s worldwide registrations and any actions taken for reasons of safety;
  
• a summary of all safety data collated in the review period, and a cumulative review of data collected since marketing authorization;
  
• a conclusion indicating whether the product’s labeling and promotional literature require updating, or sufficiently describe the known risks associated with product use.

The Periodic Safety Update Report (PSUR) is the main post-marketing pharmacovigilance document required throughout the product’s post-marketing life in the EU.

In the US, submission of a New Drug Application (NDA) Periodic Adverse Drug Experience Report (PADER) fulfils the same purpose as a PSUR in the EU. However, it is worth noting that, for reasons of practicality, if an EU PSUR already exists for a given product, it is common practice for the Food and Drug Administration (FDA) to permit submission of the EU PSUR (through application for a waiver) in place of a US PADER, thereby relieving the MAH of the burden of preparing two separate periodic reports for the same product.

A summary of the general structure of a PSUR and PADER is presented in Table 5.1, to highlight the key differences in the format of these documents.

Table 5.1 The EU PSUR and US PADER – key differences in content.

In addition to timely submission of PSURs/PADER according to the applicable scheduling and periodicity, additional submission of PSURs with PSUR Addendums and Summary Bridging Reports (SBRs) is required in cases of:

• license renewals;
  
• registrations of the product in new countries;
  
• registration of new indications in markets where the product is already registered.

In such cases, a PSUR Addendum report is required to accompany submission of a 6-monthly or 1-year PSUR that is more than 3 months outside Data Lock Point (DLP), or a 3-year PSUR that is more than 6 months outside the DLP. A SBR is required for submissions that contain more than one PSUR, or contain one PSUR and a PSUR Addendum. Further to the PSURs, PSUR Addendums, and SBRs, the MAH may need to prepare ad-hoc safety reviews and update Risk Management Plans (RMP) and Benefit-Risk Evaluation Reports throughout the product’s post-marketing life. RMPs and Benefit-Risk Evaluation Reports are discussed in Chapter 4 (Pharmacovigilance Medical Writing in Risk Evaluation and Management) and ad-hoc safety summaries in Chapter 6 (The Ad-hoc Safety Review and Response to Questions Document).

To summarize, the following pharmacovigilance documents are required in the post-marketing life of a medicinal product (see Figure 1.1.):

• PSUR/PADER;
  
• PSUR Addendum;
  
• SBR;
  
• RMP and Benefit-Risk Evaluation Reports;
  
• Ad-hoc safety reviews.

5.2 The EU Periodic Safety Update Report

The key general principles for EU PSURs, as defined by Volume 9A and ICH E2C, are summarized in Table 5.2.

Table 5.2 General principles for the EU PSUR.

5.2.2 Scheduling and Periodicity – When are EU PSURs Prepared?

EU regulations require PSURs to be submitted for approved drugs in accordance with the scheduling summarized in Figure 5.1.

Figure 5.1 PSUR scheduling in the EU region.

In addition to the above International Birth Date (IBD)-based scheduling of EU PSUR submissions, the MAH can also be required to submit a PSUR outside this schedule upon a request by a regulatory authority.

5.2.2.1 Exceptions to Standard EU PSUR Scheduling

There are a number of situations when the clock on PSUR scheduling described above can be re-started, and a product that had progressed to yearly or 3-yearly submission intervals can be taken back to the initial 6-monthly schedule of the first 2 years. These include:

• registration of a new indication or treatment population;
  
• registration of a new dose or method of administration;
  
• an updated RMP requiring specific monitoring of a safety concern;
  
• a new active substance that is a different salt/ester of the original active ingredient;
  
• a new excipient lacking an established safety profile.

5.2.3 Data Sources for the EU PSUR

A summary of the data required before embarking on PSUR preparation is presented in Table 5.3. The departments responsible for supplying each piece of source data will invariably be known by varying titles in different companies, but will largely follow the same pattern. It is also worth noting that different competent authorities within the EU may ask for additional line listings and summary tabulation outside the standard ICH E2C (R1) output presented in Table 5.3.

Table 5.3 Source data for the EU PSUR.

5.2.4 Review of EU PSURs

The preparation of an EU PSUR is a multidisciplinary team effort and personnel from several departments will be tasked with provision of source data, review, and approval of PSUR sections pertinent to their respective areas of responsibility.

The team involved in a representative PSUR review and approval is presented in Table 5.4.

Table 5.4 The EU PSUR review team.

5.2.5 A Timeline – Planning for the EU PSUR

Preparation of the PSUR comprises four key activities, namely:

• PSUR planning and collation of source data;
  
• writing of the draft PSUR;
  
• review of the draft PSUR;
  
• QC activities and PSUR finalization.

EU PSURs have to be submitted to the appropriate regulatory authority by Day 60 after the data cut-off date, referred to as the DLP. Therefore, these planning, writing, and review activities, involving an interdisciplinary team, need to be completed within a 60-day timeline. As a result, the PSUR writing process needs to be initiated some time before the DLP, as outlined in the example timeline presented in Figure 5.2.

Figure 5.2 Example timeline for EU PSUR preparation.

5.2.5.1 PSUR Planning and Collation of Source Data

At Day -30, draft ICH E2C line listings for inclusion in the PSUR (as listed in Table 5.3) need to be prepared and reviewed. Draft line listings are initially reviewed by the responsible Pharmacovigilance Officer, to ensure that all included adverse events received by the MAH during the PSUR review period were correctly coded (particularly in companies where listedness/expectedness is manually assigned to adverse events by the data entry specialist) and are appropriately presented in the line listings forming the PSUR source data and PSUR appendices. Any required corrections to the data within the MAH’s safety database need to be made at this stage, so that the PSUR author has ‘clean’ data available for the formal start of the PSUR writing process. The draft line listings should also be reviewed by the responsible Drug Safety Physician, to assess the totality and significance of safety data received by the MAH during the review period, in order to determine how any potential safety issues will be discussed/presented in the PSUR.

At Day -15, all key stakeholders in the PSUR preparation process (i.e. the Drug Safety Physician, Regulatory Affairs representative, and the Pharmacovigilance Officer) discuss all issues relating to the PSUR in question (e.g. new product registrations, marketing authorization withdrawals and relevant communications from the regulatory authorities (Regulatory Affairs), monitored safety topics (Drug Safety Physician), and any practical issues that may impact the availability of source data (the Pharmacovigilance Officer). This meeting should be organized and chaired by the responsible PV Medical Writer, who at the end of the meeting should have a complete picture of the PSUR data, any relevant safety and regulatory issues to be dealt with in the PSUR, and finally, the expected contribution from the team members.

5.2.5.2 Writing of the Draft PSUR

In general, formal writing activities commence in the first week after the DLP, as it is usually advisable to wait 3–4 days after the DLP before final line listings and summary tabulations are prepared. This is to ensure that sufficient time has been allowed for any case reports received on the actual DLP date to be entered into the MAH’s safety database and thus included in the PSUR data. Initiation of writing activities at this stage allows approximately 3 weeks for completion of the draft PSUR for preliminary review by the Drug Safety Physician.

5.2.5.3 Review of the Draft PSUR

The review process for PSURs will vary across companies, with some still using the traditional method of Word documents and comments by track changes. However, increasingly, companies are opting to use a Documentum-based electronic document management system or similar (tailored to each MAH’s needs) for review and storage of their PSURs.

5.2.5.4 QC Activities and PSUR Finalization

As a general rule, it is advisable to have the PSUR approved and signed off by the Qualified Person and/or Director responsible for safety by Day 55. This allows sufficient time for Regulatory Affairs to complete their in-house activities and submit the documents to the relevant authorities in a timely manner.

5.2.6 Generic Model of an EU PSUR

Each section of the EU PSUR is reviewed in this generic model, with a summary of the data to be presented in the section together with the key messages that should be highlighted.

Periodic Safety Update Report

[Generic Product Name]

Period Covered by this Report	dd month year to dd month year
International Birth Date	dd month year
Data Lock Point	dd month year
Version, Date of Report	Final, dd month year

[MAH’s Name and Address]

[MAH’s confidentiality statement]

Table of Contents

Abbreviations

Executive Summary

1 Introduction

2 Worldwide Marketing Authorization Status

3 Update of Regulatory or Marketing Authorization Holder Actions taken for Reasons of Safety

4 Changes to the Reference Safety Information

5 Patient Exposure

5.1 Post-marketing Exposure

5.2 Clinical Trial Exposure

6 Presentation of Individual Case Histories

6.1 Scope of Presented Data and General Considerations

6.2 Presentation of Line Listings

6.3 Summary Tabulations

6.4 Analysis of Individual Case Reports

7 Studies

7.1 Newly Analyzed Company-Sponsored Studies

7.2 Targeted Safety Studies

7.3 Published Safety Studies

8 Other Information

8.1 Efficacy-related Information

8.2 Late-breaking Information

8.3 Risk Management Plans

8.4 Benefit-Risk Evaluation Reports

9 Overall Safety Evaluation

9.1 Changes in Listed Reactions

9.2 Serious Unlisted Reactions

9.3 Non-serious Unlisted Reactions

9.4 Consumer Reports

9.5 Drug Interactions

9.6 Experience with Overdose, Deliberate or Accidental

9.7 Drug Abuse and Misuse

9.8 Medication Errors

9.9 Experience with Pregnancy and Lactation

9.10 Experience in Special Patient Groups

9.11 Effects of Long-term Treatment

10 Conclusions

11 Appendices

Abbreviations

Insert a standard abbreviations and definitions table as follows.

Abbreviation	Definition
ADR	Adverse drug reaction
AE	Adverse event
CCSI	Company Core Safety Information
CIOMS	Council for International Organizations of Medical Sciences
DLP	Data Lock Point
EU	European Union
HCP	Healthcare Professional
IBD	International Birth Date
ICH	International Conference on Harmonisation
MAH	Marketing Authorization Application
MedDRA	Medical Dictionary for Regulatory Activities
PSUR	Periodic Safety Update Report
PT	Preferred term
RA	Regulatory Authority
RMP	Risk Management Plan
RSI	Reference Safety Information
SOC	System Organ Class
TTO	Time-to-onset
WWMA	Worldwide Marketing Authorization
Note: The table needs to be expanded and completed as required.

Executive Summary

The executive summary should act as a stand-alone section that provides a concise summary of the information presented in the PSUR for the review period. The executive summary is usually 1–2 pages in length and includes a summary from each of these PSUR sections:

• introductory section stating the PSUR number, scope of presented data, the product’s history and approved indications;
  
• changes to marketing authorizations;
  
• regulatory or MAH actions taken for reasons of safety;
  
• changes to the Reference Safety Information (RSI);
  
• patient exposure;
  
• summary and number of cases presented in the PSUR;
  
• overall conclusion, with a summary any actions (if any) to be undertaken by the MAH.

1 Introduction

The introduction of the PSUR should briefly (approximately to of a page) describe the product for which it is prepared (i.e. the active ingredient, therapeutic class, mechanism of action/pharmacology, approved indications, and recommended treatment doses).

The introduction should also state the review period covered (e.g. ‘this PSUR covers the 1-year period from 1 January 2010 to 31 December 2010’) and the data presented (e.g. ‘this PSUR for Product X includes all case reports received from the marketplace, regulatory authorities, the literature, clinical studies, and licensing partners’).

Although each PSUR is intended to be a ‘stand-alone’ document, the introduction should place the current PSUR in the context of previously submitted PSURs (e.g. ‘this is the 4th PSUR submitted for Product X’). In addition, the MAH should clearly state if any of the company’s products with the same active ingredient have been excluded from the PSUR and the rationale for the exclusions. Given the complicated nature of present-day marketing relationships, the MAH should also state if PSURs prepared by their licensing partners may include some of the data presented in the PSUR.

2 Worldwide Marketing Authorization Status

The Worldwide Marketing Authorization (WWMA) status presents a cumulative and up-to-date picture of the product’s marketing history, broken down by country, and is usually included as a table in the PSUR appendices (Appendix 1 in this generic PSUR model). However, this should be at the PV Medical Writer’s discretion – an appendix is not necessary for products only licensed for a few indications in a few countries; and in such cases, the WWMA status table can be presented as an in-text table in this section of the PSUR.

The WWMA status table should be formatted to show the following information for each country (presented in chronological order of the marketing authorizations) where the product is marketed:

• dates of marketing authorizations and renewals;
  
• any restrictions/qualifications on the marketing authorization that pertain to safety;
  
• approved indications and treatment populations;
  
• failed applications for marketing authorization (with rationale);
  
• MAH withdrawal of applications for marketing authorization (with rationale);
  
• withdrawal of marketing authorization;
  
• registered brand/trade names and launch dates.

3 Update of Regulatory Authority or Marketing Authorization Holder Actions taken for Reasons of Safety

This section of the PSUR presents a summary of any actions, relating to any region where the product is registered, that were instigated by a regulatory authority or proactively undertaken by the MAH for safety reasons during the PSUR review period.

The PV Medical Writer should start with a checklist to be verified during the PSUR preparation meeting and should include checks for:

• withdrawal or suspension of marketing authorizations;
  
• failure to obtain renewal of marketing authorization;
  
• any restrictions placed on product distribution;
  
• suspension/early termination of clinical studies;
  
• modification of the recommended treatment doses;
  
• changes in the target population and/or approved indications;
  
• changes in product formulation.

The rationale for any of these actions undertaken for reasons of safety should be clearly outlined in this section, and any related documentation appended to the PSUR (in addition to the standard PSUR appendices). This could include a sample copy of communications with healthcare professionals in a ‘Dear Doctor Letter’, more formally known as a Direct Healthcare Professional Communication.

In situations where no such actions were undertaken, a standard statement, categorically and specifically stating that none of the above occurred during the PSUR review period, is used in this section of the PSUR.

4 Changes to the Reference Safety Information

As the key purpose of PSURs is to allow the MAH and regulatory authority early detection of any changes in the product’s known safety profile; a reference safety document, referred to as the RSI, which describes the known adverse events associated with the product, is required for this process. For the purpose of PSURs, the RSI is usually the Company Core Safety Information (CCSI), which is developed from the MAH’s Company Core Data Sheet, the reference document that summarizes information relating to safety, indications, posology, and method of administration, pharmacology, and pharmaceutical characteristics.

Adverse events included in the CCSI for a medicinal product are referred to as ‘listed’ or ‘labeled’ adverse events, and any reported adverse event that is not listed in the CCSI (or RSI) is referred to as ‘unlisted’ or ‘unlabeled’ (instead of the ‘expected’ and ‘unexpected’ terminology used in clinical studies).

In this section of the PSUR, the document (with version and date) used as the RSI for the product needs to be stated, and any changes made to the safety information of the RSI described with a clear rationale for implementation of these changes (e.g. inclusion of new adverse drug reactions [ADR], and warnings of drug interactions, contraindications, and special precautions). A copy of the current RSI is always appended to the PSUR.

If the RSI is updated during the PSUR review period for a 6-monthly or 1-year PSUR, the CCSI in effect at the start of the review period is used as the RSI. For PSURs covering a review period longer than 1 year (i.e. the 3-year PSURs), the updated CCSI in effect at the end of the review period can be used as the RSI.

5 Patient Exposure

Safety data in EU PSURs are always presented in the context of patient exposure, both from ongoing clinical studies and the marketplace, as a means of quantifying the risk presented by the reported adverse events. Therefore, this section can be further subdivided into:

5.1 Post-marketing Exposure

Data regarding patient exposure in the marketplace during the review period can be calculated from:

• number of units (tablets, packs, etc.) of product sold;
  
• number of prescriptions written.

The number of units sold or prescriptions written during the review period is used to estimate the number of actual patients treated, using a formula based on the maximum recommended dose and treatment duration. It is important to note that the calculated patient exposure is always going to be an estimation, as the number of units sold and prescriptions written may not be fully recorded, and sold units or prescriptions written may not represent full use of the actual product.

The formula used to estimate patient exposure by the MAH should be described (including all assumptions used) in this section of the PSUR (and referenced if it is the standard method for this class of medicinal product) and should be used consistently for all PSURs prepared for the product. Where applicable and when possible, patient exposure should be broken down to show adult and paediatric exposure. Presentation of patient exposure data in a tabulation format in this section should be considered as it can improve clarity. An example of such a tabulation is presented below in Table 1.

Table 1 Patient exposure for Product X during the period under review

Product Formulation	Units Sold	Patient Exposure (in treatment-months or treatment-years)
Adult formulation
Paediatric formulation
Note: The calculation of patient exposure from the sales data needs to be explained in a footnote.

In addition to the presentation of patient exposure by paediatric and adult use where appropriate, patient exposure can also be broken down according to country; this is useful in cases of products registered for different indications in different countries, as it can permit closer assessment of reported adverse events by indications, and allow different regulatory authorities a closer inspection of the picture as it pertains to their region.

5.2 Clinical Trial Exposure

This section should present details of patient exposure from clinical studies, which is provided by the Clinical Operations department during the PSUR planning period. When there are a large number of clinical studies, the data relating to exposure in clinical studies should be presented as a table (Appendix 3 in this generic PSUR template) in the appendices, showing for each study:

• the study title/name/number;
  
• the number of planned patients;
  
• number of patients exposed to treatment during the review period;
  
• number of patients exposed to placebo or an active comparator;
  
• cumulative number of patient exposed to treatment.

It is important to ensure that there is consistency in the reported patient exposure, both clinical and post-marketing, across all PSURs for a given product. For example, updated information regarding patient exposure in studies reported in one PSUR needs be presented in all subsequent PSURs until study completion is confirmed, at which point the Clinical Study Report conclusions are also presented in the PSUR).

6 Presentation of Individual Case Histories

This section of the PSUR provides first an overview of all cases collected by the MAH in the review period followed by a summary of selected cases. This section can be divided into the following subsections:

6.1 Scope of Presented Data and General Considerations

This section of the PSUR presents an overview of the scope of data included in the PSUR, as illustrated in the example below:

Safety data presented in this PSUR includes all cases containing:

• all serious and non-serious adverse events from all spontaneous sources (including healthcare professionals, regulatory authorities, the literature, and consumers);
  
• all serious adverse events from clinical trials, patient registries, and post-marketing studies that were considered as attributable to the drug by the investigator or the MAH, or for which a reporter causality was not provided.

6.2 Presentation of Line Listings

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