VII.B.5. Format and contents of the PSUR

Location:
VII.B.

The PSUR shall be based on all available data and shall focus on new information which has emerged since the data lock point of the last PSUR [IR Art 34(1)]. Cumulative information should be taken into account when performing the overall safety evaluation and integrated benefit-risk assessment.

Because clinical development of a medicinal product frequently continues following marketing authorisation, relevant information from post-authorisation studies or clinical trials in unauthorised indications or populations should also be included in the PSUR. Similarly, as knowledge of the safety of a medicinal product may be derived from evaluation of other data associated with off-label use, such knowledge should be reflected in the risk evaluation where relevant and appropriate.

The PSUR shall provide summaries of data relevant to the benefits and risks of the medicinal product, including results of all studies with a consideration of their potential impact on the marketing authorisation [DIR Art 107b(1)(a)].

Examples of sources of efficacy, effectiveness and safety information that may be used in the preparation of PSURs include the following:

  • non-clinical studies;
  • spontaneous reports (e.g. on the marketing authorisation holder’s safety database);
  • active surveillance systems (e.g. sentinel sites);
  • investigations of product quality;
  • product usage data and drug utilisation information;
  • clinical trials, including research in unauthorised indications or populations;
  • observational studies, including registries;
  • patient support programs;
  • systematic reviews and meta-analysis;
  • marketing authorisation holders sponsored websites5 ;
  • published scientific literature or reports from abstracts, including information presented at scientific meetings;
  • unpublished manuscripts;
  • licensing partners, other sponsors or academic institutions and research networks;
  • competent authorities (worldwide).

The above list is not intended to be all inclusive, and additional data sources may be used by the marketing authorisation holder to present safety, efficacy and effectiveness information in the PSUR and to evaluate the risk-benefit balance, as appropriate to the product and its known and emerging important benefits and risks. When desired by the marketing authorisation holder, a list of the sources of information used to prepare the PSUR can be provided as an appendix to the PSUR.

A PSUR shall be prepared following the full modular structure set out in Annex II of the IR [IR Art 35].

For the purposes of this Module, sources of information include data regarding the active substance(s) included in the medicinal product, or the medicinal product that the marketing authorisation holder may reasonably be expected to have access to and that are relevant to the evaluation of the safety, and/or risk-benefit balance. It is therefore recognised that while the same format (as defined in the IR) shall be followed for all products, the extent of the information provided may vary where justified according to what is accessible to the marketing authorisation holder. For example, for a marketing authorisation holder sponsored clinical trial, there should be access to patient level data while for a clinical trial not sponsored by the marketing authorisation holder, only the published report may be accessible.

The level of detail provided in certain sections of the PSUR should depend on known or emerging important information on the medicinal product’s benefits and risks. This approach is applicable to those sections of the PSUR in which there is evaluation of information about safety, efficacy, effectiveness, safety signals and risk-benefit balance.

When preparing the PSUR, the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)) on PBRER should also be applied. Guidance on the titles, order and content of the PSUR sections is provided in VII.B.5.1. to VII.B.5.21.. When no relevant information is available for any of the sections, this should be stated.

Part I: Title page including signature6

Part II: Executive Summary

Part III: Table of Contents

1. Introduction

2. Worldwide marketing authorisation status

3. Actions taken in the reporting interval for safety reasons

4. Changes to reference safety information

5. Estimated exposure and use patterns

5.1. Cumulative subject exposure in clinical trials

5.2. Cumulative and interval patient exposure from marketing experience

6. Data in summary tabulations

6.1. Reference information

6.2. Cumulative summary tabulations of serious adverse events from clinical trials

6.3. Cumulative and interval summary tabulations from post-marketing data sources

7. Summaries of significant findings from clinical trials during the reporting interval

7.1. Completed clinical trials

7.2. Ongoing clinical trials

7.3. Long-term follow-up

7.4. Other therapeutic use of medicinal product

7.5. New safety data related to fixed combination therapies

8. Findings from non-interventional studies

9. Information from other clinical trials and sources

9.1. Other clinical trials

9.2. Medication errors

10. Non-clinical Data

11. Literature

12. Other periodic reports

13. Lack of efficacy in controlled clinical trials

14. Late-breaking information

15. Overview of signals: new, ongoing or closed

16. Signal and risk evaluation

16.1. Summaries of safety concerns

16.2. Signal evaluation

16.3. Evaluation of risks and new information

16.4. Characterisation of risks

16.5. Effectiveness of risk minimisation (if applicable)

17. Benefit evaluation

17.1. Important baseline efficacy and effectiveness information

17.2. Newly identified information on efficacy and effectiveness

17.3. Characterisation of benefits

18. Integrated benefit-risk analysis for authorised indications

18.1. Benefit-risk context – Medical need and important alternatives

18.2. Benefit-risk analysis evaluation

19. Conclusions and actions

20. Appendices to the PSUR

PSUR title page

The title page should include the name of the medicinal product(s)7 and substance, international birth date (IBD) (the date of the first marketing authorisation for any product containing the active substance granted to any company in any country in the world), reporting interval, date of the report, marketing authorisation holder details and statement of confidentiality of the information included in the PSUR.

The title page shall also contain the signature.

PSUR executive summary

An executive summary should be placed immediately after the title page and before the table of contents. The purpose of the executive summary is to provide a concise summary of the content and the most important information in the PSUR and should contain the following information:

  • introduction and reporting interval;
  • medicinal product(s), therapeutic class(es), mechanism(s) of action, indication(s), pharmaceutical formulation(s), dose(s) and route(s) of administration;
  • estimated cumulative clinical trials exposure;
  • estimated interval and cumulative exposure from marketing experience;
  • number of countries in which the medicinal product is authorised;
  • summary of the overall benefit-risk analysis evaluation (based on sub-section 18.2 “benefit-risk analysis evaluation” of the PSUR);
  • actions taken and proposed for safety reasons, (e.g. significant changes to the reference product information, or other risk minimisation activities);
  • conclusions.

PSUR table of contents

The executive summary should be followed by the table of contents.

VII.B.5.1. PSUR section “Introduction”

The marketing authorisation holder should briefly introduce the product(s) so that the PSUR “stands alone” but it is also placed in perspective relative to previous PSURs and circumstances. The introduction should contain the following information:

  • IBD, and reporting interval;
  • medicinal product(s), therapeutic class(es), mechanism(s) of action, authorised indication(s), pharmaceutical form(s), dose(s) and route(s) of administration;
  • a brief description of the population(s) being treated and studied;

VII.B.5.2. PSUR section “Worldwide marketing authorisation status”

This section of the PSUR should contain a brief narrative overview including: date of the first authorisation worldwide, indications(s), authorised dose(s), and where authorised.

VII.B.5.3. PSUR section “Actions taken in the reporting interval for safety reasons”

This section of the PSUR should include a description of significant actions related to safety that have been taken worldwide during the reporting interval, related to either investigational uses or marketing experience by the marketing authorisation holder, sponsors of clinical trial(s), data monitoring committees, ethics committees or competent authorities that had either:

  • a significant influence on the risk-benefit balance of the authorised medicinal product; and/or
  • an impact on the conduct of a specific clinical trial(s) or on the overall clinical development programme.

If known, the reason for each action should be provided and any additional relevant information should be included as appropriate. Relevant updates to previous actions should also be summarised in this section.

Examples of significant actions taken for safety reasons include:

Actions related to investigational uses:

  • refusal to authorise a clinical trial for ethical or safety reasons;
  • partial8 or complete clinical trial suspension or early termination of an ongoing clinical trial because of safety findings or lack of efficacy;
  • recall of investigational drug or comparator;
  • failure to obtain marketing authorisation for a tested indication including voluntary withdrawal of a marketing authorisation application;
  • risk management activities, including:
    • protocol modifications due to safety or efficacy concerns (e.g. dosage changes, changes in study inclusion/exclusion criteria, intensification of subject monitoring, limitation in trial duration);
    • restrictions in study population or indications;
    • changes to the informed consent document relating to safety concerns;
    • formulation changes;
    • addition by regulators of a special safety-related reporting requirement;
    • issuance of a communication to investigators or healthcare professionals; and
    • plans for new studies to address safety concerns.

Actions related to marketing experience:

  • failure to obtain or apply for a marketing authorisation renewal;
  • withdrawal or suspension of a marketing authorisation;
  • actions taken due to product defects and quality issues;
  • suspension of supply by the marketing authorisation holder;
  • risk management activities including:
    • significant restrictions on distribution or introduction of other risk minimisation measures;
    • significant safety-related changes in labelling documents including restrictions on use or population treated;
    • communications to health care professionals; and
    • new post-marketing study requirement(s) imposed by competent authorities.

VII.B.5.4. PSUR section “Changes to reference safety information”

This PSUR section should list any significant changes made to the reference safety information within the reporting interval. Such changes might include information relating to contraindications, warnings, precautions, serious adverse drug reactions, interactions, important findings from ongoing or completed clinical trials and significant non-clinical findings (e.g. carcinogenicity studies). Specific information relevant to these changes should be provided in the appropriate sections of the PSUR.

VII.B.5.5. PSUR section “Estimated exposure and use patterns”

PSURs shall provide an accurate estimate of the population exposed to the medicinal product, including all data relating to the volume of sales and volume of prescriptions. This estimate of exposure shall be accompanied by a qualitative and quantitative analysis of actual use, which shall indicate, where appropriate, how actual use differs from the indicated use based on all data available to the marketing authorisation holder, including the results of observational or drug utilisation studies [IR Art 34 (2)].

This PSUR section should provide estimates of the size and nature of the population exposed to the medicinal product including a brief description of the method(s) used to estimate the subject/patient exposure and the limitations of that method.

Consistent methods for calculating subject/patient exposure should be used across PSURs for the same medicinal product. If a change in the method is appropriate, both methods and calculations should be provided in the PSUR introducing the change and any important difference between the results using the two methods should be highlighted.

VII.B.5.5.1. PSUR sub-section “Cumulative subject exposure in clinical trials”

This section of the PSUR should contain the following information on the patients studied in clinical trials sponsored by the marketing authorisation holder, if applicable presented in tabular formats:

  • cumulative numbers of subjects from ongoing and completed clinical trials exposed to the investigational medicinal product, placebo, and/or active comparator(s) since the DIBD. It is recognised that for “old products”, detailed data might not be available;
  • more detailed cumulative subject exposure in clinical trials should be presented if available (e.g. sub-grouped by age, sex, and racial/ethnic group for the entire development programme);
  • important differences among trials in dose, routes of administration, or patient populations can be noted in the tables, if applicable, or separate tables can be considered;
  • if clinical trials have been or are being performed in special populations (e.g. pregnant women; patients with renal, hepatic, or cardiac impairment; or patients with relevant genetic polymorphisms), exposure data should be provided as appropriate;
  • when there are substantial differences in time of exposure between subjects randomised to the investigational medicinal product or comparator(s), or disparities in length of exposure between clinical trials, it can be useful to express exposure in subject-time (subject-days, -months, or – years);
  • investigational drug exposure in healthy volunteers might be less relevant to the overall safety profile, depending on the type of adverse reaction, particularly when subjects are exposed to a single dose. Such data can be presented separately with an explanation as appropriate;
  • if the serious adverse events from clinical trials are presented by indication in the summary tabulations, the patient exposure should also be presented by indication, where available;
  • for individual trials of particular importance, demographic characteristics should be provided separately.

Examples of tabular format for the estimated exposure in clinical trials are presented in VII. Appendix 1, Tables VII.2, VII.3 and VII.4.

VII.B.5.5.2. PSUR sub-section “Cumulative and interval patient exposure from marketing experience”

Separate estimates should be provided for cumulative exposure (since the IBD), when possible, and interval exposure (since the data lock point of the previous PSUR). Although it is recognised that it is often difficult to obtain and validate exposure data, the number of patients exposed should be provided whenever possible, along with the method(s) used to determine the estimate. Justification should be provided if it is not possible to estimate the number of patients exposed. In this case, alternative estimates of exposure, if available, should be presented along with the method(s) used to derive them. Examples of alternative measures of exposure include patient-days of exposure and number of prescriptions. Only if such measures are not available, measures of drug sales, such as tonnage or dosage units, may be used.

The concept of a defined daily dose may also be used to arrive at patient exposure estimates. The data should be presented according to the following categories:

1- Post-authorisation (non-clinical trial) exposure:

An overall estimation of patient exposure should be provided. In addition, the data should be routinely presented by sex, age, indication, dose, formulation and region, where applicable. Depending upon the product, other variables may be relevant, such as number of vaccination courses, route(s) of administration, and duration of treatment. When there are patterns of reports indicating a safety signal, exposure data within relevant subgroups should be presented, if possible.

2- Post-authorisation use in special populations:

Where post-authorisation use has occurred in special populations, available information regarding cumulative patient numbers exposed and the method of calculation should be provided. Sources of such data may include for instance non-interventional studies designed to obtain this information, including registries. Other sources of information may include data collection outside a study environment including information collected through spontaneous reporting systems (e.g. information on reports of pregnancy exposure without an associated adverse event may be summarised in this section). Populations to be considered for discussion include, but might not be limited to: • paediatric population;

  • elderly population;
  • pregnant or lactating women;
  • patients with hepatic and/or renal impairment;
  • patients with other relevant co-morbidity;
  • patients with disease severity different from that studied in clinical trials;
  • sub-populations carrying relevant genetic polymorphism(s);
  • populations with specific racial and/or ethnic origins.

3- Other post-authorisation use:

If the marketing authorisation holder becomes aware of a pattern of use of the medicinal product, which may be regional, considered relevant for the interpretation of safety data, provide a brief description thereof. Examples of such patterns of use may include evidence of overdose, abuse, misuse and use beyond the recommendation(s) in the reference product information (e.g. an antiepileptic drug used for neuropathic pain and/or prophylaxis of migraine headaches). Where relevant to the evaluation of safety and/or benefit-risk, information reported on patterns of use without reference to adverse reactions should be summarised in this section as applicable. Such information may be received via spontaneous reporting systems, medical information queries, customer’s complaints, screening of digital media or via other information sources available to the marketing authorisation holder. If quantitative information on use is available, it should be provided.

If known, the marketing authorisation holder may briefly comment on whether other use beyond the recommendation(s) in the reference product information may be linked to clinical guidelines, clinical trial evidence, or an absence of authorised alternative treatments. For purposes of identifying patterns of use outside the terms of the reference product information, the marketing authorisation holder should use the appropriate sections of the reference product information that was in effect at the end of the reporting interval of the PSUR (e.g. authorised indication, route of administration, contraindications).

Signals or risks identified from any data or information source should be presented and evaluated in the relevant sections of the PSUR.

Examples of tabular format for the estimated exposure from marketing experience are presented in VII. Appendix 1, Tables VII.5 and VII.6.

VII.B.5.6. PSUR section “Data in summary tabulations”

The objective of this PSUR section is to present safety data through summary tabulations of serious adverse events from clinical trials, spontaneous serious and non-serious reactions from marketing experience (including reports from healthcare professionals, consumers, scientific literature, competent authorities (worldwide)) and serious reactions from non-interventional studies and other noninterventional solicited source. At the discretion of the marketing authorisation holder graphical displays can be used to illustrate specific aspects of the data when useful to enhance understanding.

When the Medical Dictionary for Regulatory Activities (MedDRA) terminology is used for coding the adverse event/reaction terms, the preferred term (PT) level and system organ class (SOC) should be presented in the summary tabulations.

The seriousness of the adverse events/reactions in the summary tabulations should correspond to the seriousness assigned to events/reactions included in the ICSRs using the criteria established in ICHE2A9 (see Annex IV). When serious and non-serious events/reactions are included in the same ICSR, the individual seriousness per reaction should be reflected in the summary tabulations. Seriousness should not be changed specifically for the preparation of the PSURs.

VII.B.5.6.1. PSUR sub-section “Reference information”

This sub-section of the PSUR should specify the version(s) of the coding dictionary used for presentation of adverse events/reactions.

VII.B.5.6.2. PSUR sub-section “Cumulative summary tabulations of serious adverse events from clinical trials”

This PSUR sub-section should provide background for the appendix that provides a cumulative summary tabulation of serious adverse events reported in the marketing authorisation holder’s clinical trials, from the DIBD to the data lock point of the current PSUR. The marketing authorisation holder should explain any omission of data (e.g. clinical trial data might not be available for products marketed for many years). The tabulation(s) should be organised by MedDRA SOC (listed in the internationally agreed order), for the investigational drug, as well as for the comparator arm(s) (active comparators, placebo) used in the clinical development programme. Data can be integrated across the programme. Alternatively, when useful and feasible, data can be presented by trial, indication, route of administration or other variables.

This sub-section should not serve to provide analyses or conclusions based on the serious adverse events.

The following points should be considered:

  • Causality assessment is generally useful for the evaluation of individual rare adverse drug reactions. Individual case causality assessment has less value in the analysis of aggregate data, where group comparisons of rates are possible. Therefore, the summary tabulations should include all serious adverse events and not just serious adverse reactions for the investigational drug, comparators and placebo. It may be useful to give rates by dose.
  • In general, the tabulation(s) of serious adverse events from clinical trials should include only those terms that were used in defining the case as serious and non-serious events should be included in the study reports.
  • The tabulations should include blinded and unblinded clinical trial data. Unblinded serious adverse events might originate from completed trials and individual cases that have been unblinded for safety-related reasons (e.g. expedited reporting), if applicable. Sponsors of clinical trials and marketing authorisation holders should not unblind data for the specific purpose of preparing the PSUR.
  • Certain adverse events can be excluded from the clinical trials summary tabulations, but such exclusions should be explained in the report. For example, adverse events that have been defined in the protocol as “exempt” from special collection and entry into the safety database because they are anticipated in the patient population, and those that represent study endpoints, can be excluded (e.g. deaths reported in a trial of a drug for congestive heart failure where all-cause mortality is the primary efficacy endpoint, disease progression in cancer trials).

An example of summary tabulation of serious adverse events from clinical trials can be found in VII. Appendix 1 Table VII.7.

VII.B.5.6.3. PSUR sub-section “Cumulative and interval summary tabulations from postmarketing data sources”

This sub-section of the PSUR should provide background for the appendix that provides cumulative and interval summary tabulations of adverse reactions, from the IBD to the data lock point of the current PSUR. These adverse reactions are derived from spontaneous ICSRs including reports from healthcare professionals, consumers, scientific literature, competent authorities (worldwide) and from solicited non-interventional ICSRs including those from non-interventional studies10. Serious and non-serious reactions from spontaneous sources, as well as serious adverse reactions from non-interventional studies and other non-interventional solicited sources should be presented in a single table, with interval and cumulative data presented side-by-side. The table should be organised by MedDRA SOC (listed in the internationally agreed order). For special issues or concerns, additional tabulations of adverse reactions can be presented by indication, route of administration, or other variables.

As described in ICH-E2D11 (see Annex IV) guideline, for marketed medicinal products, spontaneously reported adverse events usually imply at least a suspicion of causality by the reporter and should be considered to be suspected adverse reactions for regulatory reporting purposes.

Analysis or conclusions based on the summary tabulations should not be provided in this PSUR subsection.

An example of summary tabulations of adverse drug reactions from post-marketing data sources can be found in VII. Appendix 1 Table VII.8.

VII.B.5.7. PSUR section “Summaries of significant findings from clinical trials during the reporting interval”

This PSUR section should provide a summary of the clinically important emerging efficacy and safety findings obtained from the marketing authorisation holder’s sponsored clinical trials during the reporting interval, from the sources specified in the sub-sections listed below. When possible and relevant, data categorised by sex and age (particularly paediatrics versus adults), indication, dose, and region should be presented.

Signals arising from clinical trial sources should be tabulated in PSUR section 15 (“Overview on signals: new, ongoing or closed”). Evaluation of the signals, whether or not categorised as refuted signals or either potential or identified risk, that were closed during the reporting interval should be presented in PSUR section 16.2 (“Signal evaluation”). New information in relation to any previously known potential or identified risks and not considered to constitute a newly identified signal should be evaluated and characterised in PSUR sections 16.3 (“Evaluation of risks and new information”) and 16.4 (“Characterisation of risks”) respectively.

Findings from clinical trials not sponsored by the marketing authorisation holder should be described in the relevant sections of the PSUR.

When relevant to the benefit-risk evaluation, information on lack of efficacy from clinical trials for treatments of non-life-threatening diseases in authorised indications should also be summarised in this section. Information on lack of efficacy from clinical trials with products intended to treat or prevent serious or life-threatening illness should be summarised in section 13 (“Lack of efficacy in controlled clinical trials”) (VII.B.5.13).

Information from other clinical trials/study sources should be included in the PSUR sub-section 9.1 (“other clinical trials”) (VII.B.5.9.1).

In addition, the marketing authorisation holder should include an appendix listing the sponsored postauthorisation interventional trials with the primary aim of identifying, characterising, or quantifying a safety hazard or confirming the safety profile of the medicinal product that were completed or ongoing during the reporting interval. The listing should include the following information for each trial:

  • study ID (e.g. protocol number or other identifier);
  • study title (abbreviated study title, if applicable);
  • study type (e.g. randomised clinical trial, cohort study, case-control study);
  • population studied, including country and other relevant population descriptors (e.g. paediatric population or trial subjects with impaired renal function);
  • study start (as defined by the marketing authorisation holder) and projected completion dates;
  • status: ongoing (clinical trial has begun) or completed (clinical study report is finalised).

VII.B.5.7.1. PSUR sub-section “Completed clinical trials”

This sub-section of the PSUR should provide a brief summary of clinically important emerging efficacy and safety findings obtained from clinical trials completed during the reporting interval. This information can be presented in narrative format or as a synopsis12. It could include information that supports or refutes previously identified safety concerns as well as evidence of new safety signals.

VII.B.5.7.2. PSUR sub-section “Ongoing clinical trials”

If the marketing authorisation holder is aware of clinically important information that has arisen from ongoing clinical trials (e.g. learned through interim safety analyses or as a result of unblinding of subjects with adverse events), this sub-section should briefly summarise the concern(s). It could include information that supports or refutes previously identified safety concerns, as well as evidence of new safety signals.

VII.B.5.7.3. PSUR sub-section “Long term follow-up”

Where applicable, this sub-section should provide information from long-term follow-up of subjects from clinical trials of investigational drugs, particularly advanced therapy products (e.g. gene therapy, cell therapy products and tissue engineered products).

VII.B.5.7.4. PSUR sub-section “Other therapeutic use of medicinal product”

This sub-section of the PSUR should include clinically important safety information from other programmes conducted by the marketing authorisation holder that follow a specific protocol, with solicited reporting as per ICH-E2D13 (e.g. expanded access programmes, compassionate use programmes, particular patient use, and other organised data collection).

VII.B.5.7.5. PSUR sub-section “New safety data related to fixed combination therapies”

Unless otherwise specified by national or regional regulatory requirements, the following options can be used to present data from combination therapies:

  • If the active substance that is the subject of the PSURs is also authorised or under development as a component of a fixed combination product or a multi-drug regimen, this sub-section should summarise important safety findings from use of the combination therapy.
  • If the product itself is a fixed combination product, this PSUR sub-section should summarise important safety information arising from the individual components whether authorised or under development.

The information specific to the combination can be incorporated into a separate section(s) of the PSUR for one or all of the individual components of the combination.

VII.B.5.8. PSUR section “Findings from non-interventional studies”

This section should also summarise relevant safety information or information with potential impact in the benefit-risk assessment from marketing authorisation holder-sponsored non-interventional studies that became available during the reporting interval (e.g. observational studies, epidemiological studies, registries, and active surveillance programmes). This should include relevant information from drug utilisation studies when relevant to multiple regions.

The marketing authorisation holder should include an appendix listing marketing authorisation holdersponsored non-interventional studies conducted with the primary aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures which were completed or ongoing during the reporting interval. (see VII.B.5.7. for the information that should be included in the listing).

Final study reports completed during the reporting interval for the studies mentioned in the paragraph above should also be included in the regional appendix of the PSUR (see VII.B.5.20. and VII.C.5.4.).

Summary information based on aggregate evaluation of data generated from patient support programs may be included in this section when not presented elsewhere in the PSUR. As for other information sources, the marketing authorisation holder should present signals or risks identified from such information in the relevant sections of the PSUR.

VII.B.5.9. PSUR section “Information from other clinical trials and sources”

VII.B.5.9 1. PSUR sub-section “Other clinical trials”

This PSUR sub-section should summarise information relevant to the benefit-risk assessment of the medicinal product from other clinical trial/study sources which are accessible by the marketing authorisation holder during the reporting interval (e.g. results from pool analysis or meta-analysis of randomised clinical trials, safety information provided by co-development partners or from investigator-initiated trials).

VII.B.5.9 2. PSUR sub-section “Medication errors”

This sub-section should summarise relevant information on patterns of medication errors and potential medication errors, even when not associated with adverse outcomes. A potential medication error is the recognition of circumstances that could lead to a medication error, and may or may not involve a patient. Such information may be relevant to the interpretation of safety data or the overall benefitrisk evaluation of the medicinal product. A medication error may arise at any stage in the medication use process and may involve patients, consumers, or healthcare professionals.

VII.B.5.10. PSUR section “Non-clinical data”

This PSUR section should summarise major safety findings from non-clinical in vivo and in vitro studies (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the reporting interval. Results from studies designated to address specific safety concerns should be included in the PSUR, regardless of the outcome. Implications of these findings should be discussed in the relevant evaluation sections of the PSUR.

VII.B.5.11. PSUR section “Literature”

This PSUR section should include a summary of new and significant safety findings, either published in the peer-reviewed scientific literature or made available as unpublished manuscripts that the marketing authorisation holder became aware of during the reporting interval, when relevant to the medicinal product.

Literature searches for PSURs should be wider than those for individual adverse reaction cases as they should also include studies reporting safety outcomes in groups of subjects and other products containing the same active substance.

The special types of safety information that should be included, but which may not be found by a search constructed specifically to identify individual cases, include:

  • pregnancy outcomes (including termination) with no adverse outcomes;
  • use in paediatric populations;
  • compassionate supply, named patient use;
  • lack of efficacy;
  • asymptomatic overdose, abuse or misuse;
  • medication error where no adverse events occurred;
  • important non-clinical safety results.

If relevant and applicable, information on other active substances of the same class should be considered.

The publication reference should be provided in the style of the Vancouver Convention14,15.

VII.B.5.12. PSUR section “Other periodic reports”

This PSUR section will only apply in certain circumstances concerning fixed combination products or products with multiple indications and/or formulations where multiple PSURs are prepared in agreement with the competent authority. In general, the marketing authorisation holder should prepare a single PSUR for a single active substance (unless otherwise specified by the competent authority); however if multiple PSURs are prepared for a single medicinal product, this section should also summarise significant findings from other PSURs if they are not presented elsewhere within the report.

When available, based on the contractual agreements, the marketing authorisation holder should summarise significant findings from periodic reports provided during the reporting interval by other parties (e.g. sponsors, other marketing authorisation holders or other contractual partners).

VII.B.5.13. PSUR section “Lack of efficacy in controlled clinical trials”

This section should summarise data from clinical trials indicating lack of efficacy, or lack of efficacy relative to established therapy(ies), for products intended to treat or prevent serious or life-threatening illnesses (e.g. excess cardiovascular adverse events in a trial of a new anti-platelet medicine for acute coronary syndromes) that could reflect a significant risk to the treated population.

VII.B.5.14. PSUR section “Late-breaking information”

The marketing authorisation holder should summarise in this PSUR section the potentially important safety, efficacy and effectiveness findings that arise after the data lock point but during the period of preparation of the PSUR. Examples include clinically significant new publications, important follow-up data, clinically relevant toxicological findings and any action that the marketing authorisation holder, a data monitoring committee, or a competent authority (worldwide) has taken for safety reasons. New individual case reports should not be routinely included unless they are considered to constitute an important index case (i.e. the first instance of an important event) or an important safety signal or where they may add information to the evaluation of safety concerns already presented in the PSUR (e.g. a well documented case of aplastic anaemia in a medicinal product known to be associated with adverse effects on the bone marrow in the absence of possible alternative causes).

Any significant change proposed to the reference product information (e.g. new adverse reaction, warning or contraindication) which has occurred during this period, should also be included in this section of the PSUR (see VII.B.4.), where feasible.

The data presented in this section should also be taken into account in the evaluation of risks and new information (see VII.B.5.16.3.).

VII.B.5.15. PSUR section “Overview of signals: new, ongoing, or closed”

The general location for presentation of information on signals and risks within the PSUR is shown in figure VII.1 (see VII.B.5.21.). The purpose of this section is to provide a high level overview of signals16 that were closed (i.e. evaluation was completed) during the reporting interval as well as ongoing signals that were undergoing evaluation at the end of the reporting interval. For the purposes of the PSUR, a signal should be included once it has undergone the initial screening or clarification step, and a determination made to conduct further evaluation by the marketing authorisation holder17.It should be noted that a safety signal is not synonymous with a statistic of disproportionate reporting for a specific medicine/event combination as a validation step is required. Signals may be qualitative (e.g., a pivotal individual case safety report, case series) or quantitative (e.g. a disproportionality score, findings of a clinical trial or epidemiological study). Signals may arise in the form of an information request or inquiry on a safety issue from a competent authority (worldwide) (see Module IX).

Decisions regarding the subsequent classification of these signals and the conclusions of the evaluation, involve medical judgement and scientific interpretation of available data, which is presented in section 16 (“Signal and risk evaluation”) of the PSUR.

A new signal refers to a signal that has been identified during the reporting interval. Where new clinically significant information on a previously closed signal becomes available during the reporting interval of the PSUR, this would also be considered a new signal on the basis that a new aspect of a previously refuted signal or recognised risk warrants further action to verify. New signals may be classified as closed or ongoing, depending on the status of signal evaluation at the end of the reporting interval of the PSUR.

Examples of new signals would therefore include new information on a previously:

  • Close and refuted signal, which would result in the signal being re-opened.
  • Identified risk where the new information suggests a clinically significant difference in the severity or frequency of the risk (e.g. transient liver enzyme increases are identified risks and new information indicative of a more severe outcome such as hepatic failure is received, or neutropenia is an identified risk and a well documented case report of agranulocytosis with no presence of possible alternative causes is received).
  • Identified risk for which a higher frequency or severity of the risk is newly found (e.g. in an indicated subpopulation).
  • Potential risk which, if confirmed, would warrant a new warning, precaution, a new contraindication or restriction in indication(s) or population or other risk minimisation activities.

Within this section, or as an appendix the marketing authorisation holder should provide a tabulation of all signals ongoing or closed at the end of the reporting interval. This tabulation should include the following information:

  • a brief description of the signal;
  • date when the marketing authorisation holder became aware of the signal;
  • status of the signal at the end of the reporting interval (close or ongoing);
  • date when the signal was closed, if applicable;
  • source of the signal;
  • a brief summary of the key data;
  • plans for further evaluation; and
  • actions taken or planned.

An example of tabulation of signals can be found in VII. Appendix 2.

The detailed signal assessments for closed signals are not to be included in this section but instead should be presented in sub-section 16.2 (“Signal evaluation”) of the PSUR.

Evaluation of new information in relation to any previously known identified and potential risks and not considered to constitute a new signal should be provided in PSUR sub-section 16.3 (“Evaluation of risks and new information”).

When a competent authority (worldwide) has requested that a specific topic (not considered a signal) be monitored and reported in a PSUR, the marketing authorisation holder should summarise the result of the analysis in this section if it is negative. If the specific topic becomes a signal, it should be included in the signal tabulation and discussed in sub-section 16.2 (“Signal evaluation”).

VII.B.5.16. PSUR section “Signal and risk evaluation”

The purpose of this section of the PSUR is to provide:

  • A succinct summary of what is known about important identified and potential risks and missing information at the beginning of the reporting interval covered by the report  (VII.B.5.16.1.).
  • An evaluation of all signals closed during the reporting interval (VII.B.5.16.2.).
  • An evaluation of new information with respect to previously recognised identified and potential risks (VII.B.5.16.3).
  • An updated characterisation of important potential and identified risks, where applicable (VII.B.5.16.4.).
  • A summary of the effectiveness of risk minimisation activities in any country or region which may have utility in other countries or regions (VII.B.5.16.5.).

A flowchart illustrating the mapping of signals and risks to specific sections/sub-sections of the PSUR can be found in VII.B.5.21.

These evaluation sub-sections should not summarise or duplicate information presented in previous sections of the PSUR but should rather provide interpretation and critical appraisal of the information, with a view towards characterising the profile of those risks assessed as important. In addition, as a general rule, it is not necessary to include individual case narratives in the evaluation sections of the PSUR but where integral to the scientific analysis of a signal or risk, a clinical evaluation of pivotal or illustrative cases (e.g. the first case of suspected agranulocytosis with an active substance belonging to a class known to be associated with this adverse reaction) should be provided (see VII.B.3.).

VII.B.5.16.1. PSUR sub-section “Summary of safety concerns”

The purpose of this sub-section is to provide a summary of important safety concerns at the beginning of the reporting interval, against which new information and evaluations can be made. For products with an existing safety specification, this section can be either the same as, or derived from the safety specification summary18 that is current at the start of the reporting interval of the PSUR. It should provide the following safety information:

  • important identified risks;
  • important potential risks; and
  • missing information.

The following factors should be considered when determining the importance of each risk:

  • medical seriousness of the risk, including the impact on individual patients;
  • its frequency, predictability, preventability, and reversibility;
  • potential impact on public health (frequency; size of treated population); and
  • potential for avoidance of the use of a medicinal product with a preventive benefit due to a disproportionate public perception of risk (e.g. vaccines).

For products without an existing safety specification, this section should provide information on the important identified and potential risks and missing information associated with use of the product, based on pre- and post-authorisation experience. Important identified and potential risks may include, for example:

  • important adverse reactions;
  • interactions with other medicinal products;
  • interactions with foods and other substances;
  • • medication errors;
  • effects of occupational exposure; and
  • pharmacological class effects.

The summary on missing information should take into account whether there are critical gaps in knowledge for specific safety issues or populations that use the medicinal product.

VII.B.5.16.2. PSUR sub-section “Signal evaluation”

This sub-section of the PSUR should summarise the results of evaluations of all safety signals (whether or not classified as important) that were closed during the reporting interval. A safety signal can be closed either because it is refuted or because it is determined to be a potential or identified risk, following evaluation. The two main categories to be included in this sub-section are:

  1. Those signals that, following evaluation, have been refuted as “false” signals based on medical judgement and scientific evaluation of the currently available information.
  2. Those signals that, following evaluation, have been categorised as either a potential or identified risk, including lack of efficacy.

For both categories of closed signals, a concise description of each signal evaluation should be included in order to clearly describe the basis upon which the signal was either refuted or considered to be a potential or identified risk by the marketing authorisation holder.

It is recommended that the level of detail provided in the description of the signal evaluation should reflect the medical significance of the signal (e.g. severe, irreversible, lead to increased morbidity or mortality) and potential public health importance (e.g. wide usage, frequency, significant use outside the recommendations of the product information) and the extent of the available evidence. Where multiple evaluations will be included under both categories of closed signals, they can be presented in the following order:

  • Closed and refuted signals.
  • Closed signals that are categorised as important potential risks.
  • Closed signals that are categorised as important identified risks.
  • Closed signals that are potential risks not categorised as important.
  • Closed signals that are identified risks not categorised as important.

Where applicable the evaluations of closed signals can be presented by indication or population.

The description(s) of the signal evaluations can be included in this sub-section of the PSUR or in an appendix. Each evaluation should include the following information as appropriate:

  • source or trigger of the signal;
  • background relevant to the evaluation;
  • method(s) of evaluation, including data sources, search criteria (where applicable, the specific MedDRA terms (e.g. PTs, HLTs, SOCs, etc.) or Standardised MedDRA Queries (SMQs) that were reviewed), and analytical approaches;
  • results – a summary and critical analysis of the data considered in the signal evaluation; where integral to the assessment, this may include a description of a case series or an individual case (e.g. an index case of well documented agranulocytosis or Stevens Johnson Syndrome);
  • discussion;
  • conclusion.

Marketing authorisation holder’s evaluations and conclusions for refuted signals should be supported by data and clearly presented.

VII.B.5.16.3. PSUR sub-section “Evaluation of risks and new information”

This sub-section should provide a critical appraisal of new information relevant to previously recognised risks that is not already included in sub-section 16.2 (“Signal evaluation”).

New information that constitutes a signal with respect to a previously recognised risk or previously refuted signal should be presented in the signals tabulation (see VII.B.5.15.) and evaluated in subsection 16.2 (“Signal evaluation”), if the signal is also closed during the reporting interval of the PSUR.

Updated information on a previously recognised risk that does not constitute a signal should be included in this sub-section. Examples includes information that confirms a potential risk as an identified risk, or information which allows any other further characterisation of a previously recognised risk.

New information can be organised as follows:

  1. New information on important potential risks.
  2. New information on important identified risks.
  3. New information on other potential risks not categorised as important.
  4. New information on other identified risks not categorised as important.
  5. Update on missing information.

The focus of the evaluation(s) is on new information which has emerged during the reporting interval of the PSUR. This should be concise and interpret the impact, if any, on the understanding and characterisation of the risk. Where applicable, the evaluation will form the basis for an updated characterisation of important potential and identified risks in sub-section 16.4 (“Characterisation of risks”) of the report. It is recommended that the level of detail of the evaluation included in this subsection should be proportional to the available evidence on the risk and its medical significance and public health relevance.

The evaluation(s) of the new information and missing information update(s) can be included in this sub-section of the PSUR, or in an appendix. Each evaluation should include the following information as appropriate: • source of the new information;

  • background relevant to the evaluation;
  • method(s) of evaluation, including data sources, search criteria, and analytical approaches;
  • results – a summary and critical analysis of the data considered in the risk evaluation;
  • discussion;
  • conclusion, including whether or not the evaluation supports an update of the characterisation of any of the important potential and identified risks in sub-section 16.4 (“Characterisation of risks”).

Any new information on populations exposed or data generated to address previously missing information should be critically assessed in this sub-section. Unresolved concerns and uncertainties should be acknowledged.

This sub-section should characterise important identified and potential risks based on cumulative data (i.e. not restricted to the reporting interval), and describe missing information.

Depending on the nature of the data source, the characterisation of risk may include, where applicable:

  • frequency;
  • numbers of cases (numerator) and precision of estimate, taking into account the source of the data;
  • extent of use (denominator) expressed as numbers of patients, patient-time, etc., and precision of estimate;
  • estimate of relative risk and precision of estimate;
  • estimate of absolute risk and precision of estimate;
  • impact on the individual patient (effects on symptoms, quality or quantity of life);
  • public health impact;
  • patient characteristics relevant to risk (e.g. patient factors (age, pregnancy/lactation, hepatic/renal impairment, relevant co-morbidity, disease severity, genetic polymorphism);
  • dose, route of administration;
  • duration of treatment, risk period;
  • preventability (i.e. predictability, ability to monitor for a “sentinel” adverse reaction or laboratory marker);
  • reversibility;
  • potential mechanism; and
  • strength of evidence and its uncertainties, including analysis of conflicting evidence, if applicable.

When missing information could constitute an important risk, it should be included as a safety concern. The limitations of the safety database (in terms of number of patients studied, cumulative exposure or long term use, etc.) should be discussed.

For PSURs for products with several indications, formulations, or routes of administration, where there may be significant differences in the identified and potential risks, it may be appropriate to present risks by indication, formulation, or route of administration. Headings that could be considered include:

risks relating to the active substance;

risks related to a specific formulation or route of administration (including occupational exposure);

risks relating to a specific population; and

risks associated with non-prescription use (for compounds that are available as both prescription and non-prescription products).

VII.B.5.16.5. PSUR sub-section: “Effectiveness of risk minimisation (if applicable)”

Risk minimisation activities are public health interventions intended to prevent the occurrence of an adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity should it occur. The aim of a risk minimisation activity is to reduce the probability or severity of an adverse drug reaction. Risk minimisation activities may consist of routine risk minimisation (e.g. product labelling) or additional risk minimisation activities (e.g. Direct Healthcare Professional Communication/educational materials).

The PSUR shall contain the results of assessments of the effectiveness of risk minimisation activities relevant to the risk-benefit assessment [IR Art 34(3)].

Relevant information on the effectiveness and/or limitations of specific risk minimisation activities for important identified risks that has become available during the reporting interval should be summarised in this sub-section of the PSUR.

Insights into the effectiveness of risk minimisation activities in any country or region that may have utility in other countries or regions are of particular interest. Information may be summarised by region, if applicable and relevant.

When required for reporting in a PSUR, results of evaluations that became available during the reporting interval, which refer to an individual region should be provided in the PSUR regional appendix (see VII.B.5.20. and VII.C.5.5.).

VII.B.5.17. PSUR section “Benefit evaluation”

PSUR sub-sections 17.1 (“Important baseline efficacy and effectiveness information”) and 17.2 (“Newly identified information on efficacy and effectiveness”) provide the baseline and newly identified benefit information that support the characterisation of benefit described in sub-section 17.3 (“Characterisation of benefits”) that in turn supports the benefit-risk evaluation in section 18 (“Integrated benefit-risk analysis for authorised indications”).

VII.B.5.17.1. PSUR sub-section “Important baseline efficacy and effectiveness information”

This sub-section of the PSUR summarises information on both efficacy and effectiveness of the medicinal product at the beginning of the reporting interval and provides the basis for the benefit evaluation. This information should relate to authorised indication(s) of the medicinal product listed in the reference product information (See VII.B.4.).

For medicinal products with multiple indications, populations, and/or routes of administration, the benefit should be characterised separately by these factors when relevant.

The level of detail provided in this sub-section should be sufficient to support the characterisation of benefit in the PSUR sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk assessment in section 18 (“Integrated benefit-risk analysis for authorised indications”).

VII.B.5.17.2. PSUR sub-section “Newly identified information on efficacy and effectiveness”

For some products, additional information on efficacy or effectiveness in authorised indications may have become available during the reporting interval. Such information should be presented in this subsection of the PSUR. For authorised indications, new information on efficacy and effectiveness under conditions of actual use should also be described in this sub-section, if available. New information on efficacy and effectiveness in uses other than the authorised indications should not be included unless relevant for the benefit-risk evaluation in the authorised indications.

Information on indications newly authorised during the reporting interval should also be included in this sub-section. The level of detail provided in this section should be sufficient to support the characterisation of benefit in sub-section 17.3 (“Characterisation of benefits”) and the benefit-risk assessment in section 18 (“Integrated benefit-risk analysis for authorised indications”).

In this sub-section, particular attention should be given to vaccines, anti-infective agents or other medicinal products where changes in the therapeutic environment may impact on efficacy/effectiveness over time.

VII.B.5.17.3. PSUR sub-section “Characterisation of benefits”

This sub-section provides an integration of the baseline benefit information and the new benefit information that has become available during the reporting interval, for authorised indications.

The level of detail provided in this sub-section should be sufficient to support the analysis of benefitrisk in section 18 (“Integrated benefit-risk analysis for authorised indications”).

When there are no new relevant benefit data, this sub-section should provide a characterisation of the information in sub-section 17.1 (“Important baseline efficacy and effectiveness information”).

When there is new positive benefit information and no significant change in the risk profile in this reporting interval, the integration of baseline and new information in this sub-section should be succinct.

This sub-section should provide a concise but critical evaluation of the strengths and limitations of the evidence on efficacy and effectiveness, considering the following when available:

  • a brief description of the strength of evidence of benefit, considering comparator(s), effect size, statistical rigor, methodological strengths and deficiencies, and consistency of findings across trials/studies;
  • new information that challenges the validity of a surrogate endpoint, if used;
  • clinical relevance of the effect size;
  • generalisability of treatment response across the indicated patient population (e.g. information that demonstrates lack of treatment effect in a sub-population);
  • adequacy of characterization of dose-response;
  • duration of effect;
  • comparative efficacy; and
  • a determination of the extent to which efficacy findings from clinical trials are generalisable to patient populations treated in medical practice.

VII.B.5.18. PSUR section “Integrated benefit-risk analysis for authorised indications”

The marketing authorisation holder should provide in this PSUR section an overall appraisal of the benefit and risk of the medicinal product as used in clinical practice. Whereas sub-sections 16.4 (“Characterisation of risks”) and 17.3 (“Characterisation of benefits”) present the risks and benefits, this section should provide a critical analysis and integration of the key information in the previous sections and should not simply duplicate the benefit and risk characterisation presented in the subsections mentioned above.

VII.B.5.18.1. PSUR sub-section “Benefit-risk context – medical need and important alternatives”

This sub-section of the PSUR should provide a brief description of the medical need for the medicinal product in the authorised indications and summarised alternatives (medical, surgical or other; including no treatment).

VII.B.5.18.2. PSUR sub-section “Benefit-risk analysis evaluation”

A risk-benefit balance is specific to an indication and population. Therefore, for products authorised for more than one indication, risk-benefit balances should be evaluated and presented by each indication individually. If there are important differences in the risk-benefit balance among populations within an indication, the benefit-risk evaluation should be presented by population, if possible.

The benefit-risk evaluation should be presented and discussed in a way that facilitates the comparison of benefits and risks and should take into account the following points:

  • Whereas previous sections/sub-sections should include all important benefit and risk information, not all benefits and risks contribute importantly to the overall benefit-risk evaluation, therefore, the key benefits and risks considered in the evaluation should be specified. The key information presented in the previous benefit and risk section/sub-sections should be carried forward for integration in the benefit-risk evaluation.
  • Consider the context of use of the medicinal product: the condition to be treated, prevented, or diagnosed; its severity and seriousness; and the population to be treated (relatively healthy; chronic illness, rare conditions).
  • With respect to the key benefit(s), consider its nature, clinical importance, duration, and generalisability, as well as evidence of efficacy in non-responders to other therapies and alternative treatments. Consider the effect size. If there are individual elements of benefit, consider all (e.g. for therapies for rheumatoid arthritis: reduction of symptoms and inhibition of radiographic progression of joint damage).
  • With respect to risk, consider its clinical importance, (e.g. nature of toxicity, seriousness, frequency, predictability, preventability, reversibility, impact on patients), and whether it arose from clinical trials in unauthorised indications or populations, off-label use, or misuse.
  • The strengths, weaknesses, and uncertainties of the evidence should be considered when formulating the benefit-risk evaluation. Describe how uncertainties in the benefits and risks impact the evaluation. Limitations of the assessment should be discussed.

Provide a clear explanation of the methodology and reasoning used to develop the benefit-risk evaluation:

  • The assumptions, considerations, and judgement or weighting that support the conclusions of the benefit-risk evaluation should be clear.
  • If a formal quantitative or semi-quantitative assessment of benefit-risk is provided, a summary of the methods should be included.
  • Economic considerations (e.g. cost-effectiveness) should not be considered in the benefit-risk evaluation.

When there is important new information or an ad hoc PSUR has been requested, a detailed benefitrisk analysis should be presented based on cumulative data. Conversely, where little new information has become available during the reporting interval, the primary focus of the benefit-risk evaluation might consist of an evaluation of updated interval safety data.

VII.B.5.19. PSUR section “Conclusions and actions”

A PSUR should conclude with the implications of any new information that arose during the reporting interval in terms of the overall evaluation of benefit-risk for each authorised indication, as well as for relevant subgroups, if appropriate.

Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the marketing authorisation holder should assess the need for changes to the reference product information and propose changes as appropriate.

In addition and as applicable, the conclusions should include preliminary proposal(s) to optimise or further evaluate the risk-benefit balance for further discussion with the relevant competent authority(ies). This may include proposals for additional risk minimisation activities. For products with a pharmacovigilance or risk management plan, the proposals should also be considered for incorporation into the pharmacovigilance plan and/or risk minimisation plan, as appropriate (see Module V).

Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the marketing authorisation holder shall draw conclusions in the PSUR as to the need for changes and/or actions, including implications for the approved summary of product characteristics (SmPC) for the product(s) for which the PSUR is submitted [IR Art 34(5)].

Proposed changes to the reference product information should be described in this section of the PSUR. The regional appendix should include proposals for product information (SmPC and package leaflet) together with information on ongoing changes when applicable.

VII.B.5.20. Appendices to the PSUR

A PSUR should contain the following appendices as appropriate, numbered as follows:

  1. Reference information (see VII.B.4.).
  2. Cumulative summary tabulations of serious adverse events from clinical trials; and cumulative and interval summary tabulations of serious and non-serious adverse reactions from post-marketing data sources.
  3. Tabular summary of safety signals (if not included in the body of the report)19.
  4. Listing of all the marketing authorisation holder-sponsored interventional and non-interventional studies with the primary aim of identifying, characterising, or quantifying a safety hazard or confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures, in case of non-interventional studies.
  5. List of the sources of information used to prepare the PSUR (when desired by the marketing authorisation holder).
  6. Regional appendix: The requirements for the regional appendix in the EU are provided in section VII.C.5.

VII.B.5.21. Mapping signals and risks to PSUR sections/sub-sections

The following flowchart (Figure VII.1) reflects the general location for the presentation of information on signals and risks within the PSUR.