Report CopyRight/DMCA Form For : E2c R2 Step 5 Periodic Benefit Risk Evaluation Report
One of the motivating factors behind revision of the ICH E2C R1 guideline was the desire to enhance efficiency by decreasing the duplication of effort required for the preparation of various regulatory documents This guideline has been developed therefore such that corresponding sections of the
EC2 R2 Periodic benefit risk evaluation report PBRER. Table of contents,1 Introduction 4,1 1 Background 4. 1 2 Objectives 5,1 3 Scope of the PBRER 6, 1 4 Relation of the PBRER to other ICH documents 7. 2 General principles 7,2 1 Single PBRER for an active substance 7. 2 2 PBRERs for fixed dose combination product 8, 2 3 Products manufactured and or marketed by more than one company 8. 2 4 Reference information 8,2 5 Level of detail within PBRER 9. 2 6 Efficacy Effectiveness 9,2 7 Benefit risk evaluation 10. 2 8 Periodicity and PBRER data lock point 10, 2 8 1 International birth date and data lock point 10. 2 8 2 Managing different frequencies of PBRER submission 10. 2 8 3 Time interval between data lock point and the submission 13. 2 9 Format and presentation of PBRER 13,2 9 1 Format 13. 2 9 2 Presentation 13,3 Guidance on contents of the PBRER 14. 3 1 Introduction 15,3 2 Worldwide marketing approval status 15. 3 3 Actions taken in the reporting interval for safety reasons 16. 3 4 Changes to reference safety information 17,3 5 Estimated exposure and use patterns 17. 3 5 1 Cumulative subject exposure in clinical trials 17. 3 5 2 Cumulative and interval patient exposure from marketing experience 18. 3 6 Data in summary tabulations 19,3 6 1 Reference information 19. 3 6 2 Cumulative summary tabulations of serious adverse events from clinical trials 19. 3 6 3 Cumulative and interval summary tabulations from post marketing data sources 20. 3 7 Summaries of significant safety findings from clinical trials during the reporting interval. 3 7 1 Completed clinical trials 21,3 7 2 Ongoing clinical trials 21. 3 7 3 Long term follow up 21, 3 7 4 Other therapeutic use of medicinal product 21. 3 7 5 New safety data related to fixed combination terapies 22. 3 8 Findings from non interventional studies 22, ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 2 45, 3 9 Information from other clinical trials and sources 22. 3 9 1 Other clinical trials 22,3 9 2 Medication errors 22. 3 10 Non clinical data 23,3 11 Literature 23,3 12 Other periodic reports 23. 3 13 Lack of efficacy in controlled clinical trials 23. 3 14 Late breaking information 23,3 15 Overview of signals new ongoing or closed 24. 3 16 Signal and risk evaluation 25,3 16 1 Summary of safety concerns 25. 3 16 2 Signal evaluation 26,3 16 3 Evaluation of risks and new information 27. 3 16 4 Characterisation of risks 28, 3 16 5 Effectiveness of risk minimisation if applicable 29. 3 17 Benefit evaluation 29, 3 17 1 Important baseline efficacy effectiveness information 29. 3 17 2 Newly identified information on efficacy effectiveness 30. 3 17 3 Characterisation of benefits 30, 3 18 Integrated benefit risk analysis for approved indications 31. 3 18 1 Benefit risk context medical need and important alternatives 31. 3 18 2 Benefit risk analysis evaluation 31,3 19 Conclusions and actions 32. 3 20 Appendices to the PBRER 32,4 Appendices to this guideline 32. Appendix A 34,Appendix B 37,Appendix C 40,Appendix D 42. Appendix E 44,Appendix F 45, ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 3 45,1 Introduction, The Periodic Benefit Risk Evaluation Report PBRER described in this guideline is intended to be a. common standard for periodic benefit risk evaluation reporting on marketed products including. approved drugs that are under further study among the ICH regions. This guideline defines the recommended format and content of a PBRER and provides an outline of. points to be considered in its preparation and submission. Definitions of many technical terms used in the guideline are included in a glossary Appendix A the. first mention of a term in the guideline is identified with an asterisk. 1 1 Background, When a new medicinal product is approved for marketing demonstration of safety and efficacy are. generally based on data from a limited number of patients many studied under the controlled. conditions of randomised trials Often higher risk subgroups and patients with concomitant illnesses. that require use of other drugs are excluded from clinical trials and long term treatment data are. limited Moreover patients in trials are closely monitored for evidence of adverse events In clinical. practice monitoring is less intensive a broader range of patients are treated age co morbidities. drugs genetic abnormalities and events too rare to occur in clinical trials may be observed e g. severe liver injury These factors underlie the need for continuing analysis of relevant safety. efficacy and effectiveness1 information throughout the lifecycle of a medicinal product promptly as. important findings occur and periodically to allow an overall assessment of the accumulating data. Although the majority of new information will be safety related new information about effectiveness. limitations of use alternative treatments and many other aspects of the drug s place in therapy may. be pertinent to its benefit risk assessment, The ICH Guideline E2C Clinical Safety Data Management Periodic Safety Update Reports for Marketed. Drugs achieved Step 4 in 1996 and was intended to harmonise the periodic reporting requirements to. regulatory authorities and to provide in a common format the worldwide interval safety experience of. a medicinal product at defined times post approval At that time the focus of the Periodic Safety. Update Report PSUR was on relevant new safety information in the context of patient exposure to. determine if changes were needed to the reference safety information RSI in order to optimise the. continued safe use of the product The guideline was revised in 2003 to provide needed clarification. guidance and flexibility, Since that time the pharmacovigilance environment has evolved prompting reassessment of the role. of the PSUR in the spectrum of safety documents submitted to regulatory authorities This. reassessment highlighted several factors that led to consensus for revision and refocus of the. guideline to enhance its usefulness in light of advances in the field. Significant progress in the technology and science of pharmacovigilance including electronic. submission of individual case safety reports ICSRs to regulatory authorities automated data. mining techniques and more attention to benefit risk evaluation. Greater emphasis on proactive and documented risk management planning. Increasing recognition that meaningful evaluation of important new risk information should be. undertaken in the context of a medicinal product s benefits and. Overlap in the content of ICH Guidelines related to pharmacovigilance documentation. The terms efficacy and effectiveness are not standardised and have different meanings across some regions See Section. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 4 45, As noted above the primary objective of the PSUR was to provide a comprehensive picture of the. safety of approved medicinal products With recognition that the assessment of the risk of a medicinal. product is most meaningful when considered in light of its benefits the proposed report would provide. greater emphasis on benefit than the PSUR particularly when risk estimates change importantly In. such cases there will need to be an overall explicit evaluation of benefit risk Consequently the name. of the proposed report is the Periodic Benefit Risk Evaluation Report PBRER The PBRER would also. provide greater emphasis on the cumulative knowledge regarding a medicinal product while retaining. a focus on new information, A formal evaluation of benefit is a new feature of the PBRER however it is recognised that a concise. discussion of benefit will usually be sufficient unless the safety or benefit risk profile has changed. significantly during the reporting interval Thus the level of detail provided in certain sections of the. PBRER e g evaluation of safety and efficacy data evaluation of safety signals and benefit risk. evaluation should be proportional to the medicinal product s known or emerging important risks and. to evidence of emerging important benefits, As the scope of the PBRER has been extended to include benefit as well as safety the reference. information for the report also needs to take this new factor into account It is generally impractical. for marketing authorisation holders MAHs to have one reference information source that. encompasses all parameters that contribute towards the benefit risk evaluation i e benefit. efficacy effectiveness indication s and safety information. is common to all ICH regions and, addresses all circumstances e g generics products licensed in one country only. Therefore this guideline proposes more practical options that MAHs can consider in selecting the most. appropriate reference product information for the PBRER These proposals incorporate the original ICH. E2C concept of reference safety information e g Company Core Safety Information CCSI with. the addition of the approved indications for the product This reference product information may be. the Company Core Data Sheet CCDS or another document proposed by the MAH see Section 2 4. The important baseline efficacy and effectiveness information summarised in section 17 1 of the PBRER. will form the basis or reference for the benefit evaluation irrespective of the reference product. information used by the MAH, The frequency of submission of reports to regulatory authorities is subject to national or regional. regulatory requirements and may differ depending on a number of factors The guideline includes. advice on managing different frequencies of PBRER submission in different regions. One of the motivating factors behind revision of the ICH E2C R1 guideline was the desire to enhance. efficiency by decreasing the duplication of effort required for the preparation of various regulatory. documents This guideline has been developed therefore such that corresponding sections of the. PBRER DSUR ICH E2F and safety specification of a risk management plan ICH E2E can be identical. in content See also Section 1 4 Relation of the PBRER to Other ICH Documents. 1 2 Objectives, The main objective of a PBRER is to present a comprehensive concise and critical analysis of new or. emerging information on the risks of the medicinal product and on its benefit in approved indications. to enable an appraisal of the product s overall benefit risk profile The PBRER should contain an. evaluation of new information relevant to the medicinal product that became available to the MAH. during the reporting interval in the context of cumulative information by. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 5 45, summarising relevant new safety information that could have an impact on the benefit risk profile. of the medicinal product, summarising any important new efficacy effectiveness information that has become available. during the reporting interval, examining whether the information obtained by the MAH during the reporting interval is in accord. with previous knowledge of the medicinal product s benefit and risk profile and. where important new safety information has emerged conducting an integrated benefit risk. evaluation for approved indications, When appropriate the PBRER should include proposed action s to optimise the benefit risk profile. Urgent safety information should be reported through the appropriate mechanism the PBRER is not. intended to be used to provide initial notification of significant new safety information or to provide the. means by which new safety concerns are detected,1 3 Scope of the PBRER. The main focus of each PBRER is the evaluation of relevant new safety information from the available. data sources placed within the context of any pertinent efficacy effectiveness information that may. have become available since the international birth date IBD the date of the first marketing. approval in any country in the world or the development international birth date DIBD the date of. first authorisation for the conduct of an interventional clinical trial in any country All pertinent new. safety and efficacy effectiveness information discovered during the reporting interval should be. discussed in the appropriate sections of the PBRER. For the purposes of this guideline sources of available information refer to data regarding the active. substance s included in the medicinal product or the medicinal product that the MAH may reasonably. be expected to have access to and that are relevant to the evaluation of the safety or benefit risk. profile see also Appendix E Examples of Sources of Information That May Be Used in the Preparation. of the PBRER For example there may be less information available to the MAH regarding a generic. product as compared to a product for which the MAH is the innovator and only a published report may. be accessible for a clinical trial not sponsored by the MAH On the other hand for a MAH sponsored. clinical trial the MAH will have access to patient level data towards evaluation of the product s benefit. risk When desired by the MAH a list of the sources of information used to prepare the PBRER can be. provided as an appendix to the report, The PBRER should include cumulative knowledge of the product while retaining focus on new. information i e the overall safety evaluation and integrated benefit risk evaluation will take into. account cumulative information Because clinical development of a drug frequently continues following. marketing approval relevant information from post marketing studies or clinical trials in unapproved. indications or populations should also be included in the PBRER Similarly as knowledge of the safety. of a medicinal product may be derived from evaluation of data associated with uses other than the. approved indication s such knowledge would be reflected in the risk evaluation where relevant and. appropriate, For the purpose of this document the terms authorisation and authorised refer to clinical trials and the terms. approval and approved refer to marketing applications. This guideline should not serve to limit the scope of information to be provided in the evaluation of benefit risk of a. medicinal product Please refer to the applicable laws and regulations in the countries and regions in which the PBRER is to. be submitted, ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 6 45,1 4 Relation of the PBRER to other ICH documents. At present some ICH countries and regions accept submission of separate types of periodic reports to. fulfil national and regional requirements within the post approval period the PSUR ICH Guideline. E2C R1 for periodic reporting of the safety of approved medicinal products the DSUR ICH Guideline. E2F for periodic reporting on the safety of medicinal products that remain in clinical development and. the safety specification component of ICH Guideline E2E that might be submitted at the time of. marketing application and or PSUR submission to aid in the planning of pharmacovigilance activities. As these documents have different regulatory purposes different periodicities and can be reviewed by. different divisions within a single regulatory authority each document needs to be complete in its own. right a comprehensive document that can stand alone Nevertheless overlap and inconsistencies. between the content of the DSUR PSUR and safety specification can lead to inefficiencies in the. production of the documents by the MAH,Modular approach. This guideline aims to facilitate flexibility by encouraging the use of individual sections that are. common to more than one report modules that can be used for different regulatory authorities and. for different purposes Therefore the PBRER has been developed in such a way that the content of. several sections may be used for sections of other documents as a basis for a modular approach For. example if the DIBD of a DSUR for a medicinal product is aligned to the IBD of the PBRER for the. same product as suggested in ICH E2F the content of a number of sections of the DSUR can also be. used in the PBRER when the data lock points DLPs are the same i e when each report covers an. interval of one year based on the IBD, Appendix D of this guideline lists the PBRER sections that can be shared with either the DSUR ICH. E2F or safety specification of a risk management plan ICH E2E if appropriate. The use of common sections across the PBRER DSUR and safety specification as a modular approach. has a number of advantages, maximizes the utility of the modules across multiple regulatory documents. promotes consistency across the PBRER DSUR and Safety Specification. avoids unnecessary duplication of effort, is expected to improve efficiency for MAHs in the preparation of these documents. facilitates flexible utilisation of existing sections modules when for example the PBRER covers. different time intervals or needs to be submitted at different times to multiple different authorities. In these circumstances only modules that include new information or new evaluation would need. to be updated when submitting the PBRER, Although currently out of scope for ICH E2C R2 it is envisioned that the modular approach proposed. based on common sections across various documents will ultimately facilitate development of. electronic modules for use in future regulatory submissions. 2 General principles,2 1 Single PBRER for an active substance. The PBRER should provide information on all approved indications dosage forms and regimens for the. active substance with a single DLP In some circumstances it will be appropriate to present data by. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 7 45, indication dosage form dosing regimen or population e g children vs adults within the relevant. section s of the PBRER In exceptional cases submission of separate PBRERs might be appropriate. for example an active substance used in two formulations for systemic and topical administration in. entirely different indications In these cases the regulatory authorities should be notified and their. agreement obtained preferably at the time of approval. 2 2 PBRERs for fixed dose combination product, For combinations of substances also marketed individually information for the fixed combination may. be reported either in a separate PBRER or included as separate presentations in the report for one of. the individual substances depending on the circumstances Listing related PBRERs is considered. 2 3 Products manufactured and or marketed by more than one company. Each MAH is responsible for submitting PBRERs for its own products. When companies are involved in contractual relationships e g licensor licensee respective. responsibilities for preparation and submission of the PBRER to the regulatory authorities should be. clearly specified in the written agreement, When data received from a partner company ies might contribute meaningfully to the safety benefit. and or benefit risk analyses and influence the reporting company s product information these data. should be included and discussed in the PBRER,2 4 Reference information. An objective of a PBRER is to evaluate whether information obtained during the reporting interval is in. accord with previous knowledge on the product s benefit and risk profile and to indicate whether. changes should be made to the reference product information Having one reference source of. information that can be applied across the three ICH regions would facilitate a practical efficient and. consistent approach to the benefit risk evaluation and make the PBRER a unique report accepted in all. countries and regions, The reference product information for the PBRER would include core safety and approved. indications components In order to facilitate the assessment of benefit and benefit risk by indication. in the evaluation sections of the PBRER the reference product information document should list all. approved indications in ICH countries or regions It is likely that these indications will also apply in. other countries or regions However when the PBRER is also to be submitted to other countries in. which there are additional locally approved indications these indications may either be added to the. reference product information or handled as a regional appendix appendices as considered most. appropriate by the MAH The basis for the benefit evaluation should be the baseline important. efficacy effectiveness information summarised in Section 17 1 of the PBRER. The following possible options can be considered by MAHs in selecting the most appropriate reference. product information for a PBRER,Company Core Data Sheet. In accordance with ICH E2C R1 recommendations it is a common practice for MAHs to prepare their. own CCDS which includes sections relating to safety indications dosing pharmacology and other. information concerning the medicinal product The core safety information contained within the CCDS. is referred to as the CCSI A practical option is for MAHs to use the latest CCDS in effect at the end of. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 8 45, the reporting interval as the reference product information for both the risk sections of the PBRER as. well as the main approved indications for which benefit is evaluated. When the CCDS for a medicinal product does not contain information on approved indications the MAH. should clearly specify which document is used as the reference information for the approved. indications in the PBRER, Other options for the reference product information. When there is no CCDS or CCSI for a product e g where the product is approved in only one country. or region or for established generic products on the market for many years the MAH should clearly. specify the reference information being used This may comprise national or regional product. information such as the US Package Insert USPI or European Summary of Product Characteristics. SmPC or the Japanese package insert as appropriate The basis for the benefit evaluation should be. the baseline important efficacy effectiveness information summarised in Section 17 1 of the PBRER. Where the reference information for approved indications is a separate document to the RSI the. version current at the DLP of the PBRER should be included in Appendix 1. The MAH should continuously evaluate whether any revision of the reference product information RSI. is needed whenever new safety information is obtained throughout the reporting interval Significant. changes to the reference product information RSI made during the interval should be described in. Section 4 of the PBRER Changes to Reference Safety Information and include. changes to contraindications warnings precautions sections of the RSI. addition of ADR s and interactions, addition of important new information on use in overdose and. removal of an indication or other restrictions for safety or lack of efficacy reasons. Significant changes to the RSI made after the DLP but before submission of the PBRER should be. included in Section 14 of the report Late Breaking Information if feasible. If stipulated by applicable regional requirements the MAH should provide in a regional appendix. information on any final ongoing or proposed changes to the national or local authorised product. information,2 5 Level of detail within PBRER, The level of detail provided in certain sections of the PBRER should depend on the medicinal product s. known or emerging important benefits and risks This approach is applicable to those sections of the. PBRER in which there is evaluation of safety data efficacy effectiveness data safety signals and. benefit risk Therefore the extent of information provided in such PBRER sections will vary among. individual PBRERs, For example when there is important new safety information a detailed presentation of that. information should be included plus the relevant benefit information in order to facilitate a robust. benefit risk analysis Conversely when little new important safety information has become available. during the reporting interval a concise summary of baseline benefit information should be sufficient. and the benefit risk evaluation would consist primarily of an evaluation of updated interval safety data. 2 6 Efficacy Effectiveness, For the purpose of this guideline evidence on benefits in clinical trials and in everyday medical practice. should be reported Because the terms are not harmonized across regions the terms. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 9 45, efficacy effectiveness are used in this guideline to clarify that information from both clinical trials and. everyday medical practice are within the scope of the information on benefit to be included within the. PBRER In some regions efficacy refers to evidence of benefit from controlled clinical trials while. effectiveness implies use in everyday medical practice Conversely in other regions this distinction is. 2 7 Benefit risk evaluation, When a drug is approved for marketing a conclusion has been reached that when used in accordance. with approved product information its benefits outweigh its risks As new information about the drug. emerges during marketing experience benefit risk evaluation should be carried out to determine. whether benefits continue to outweigh risks and to consider whether steps need to be taken to. improve the benefit risk balance through risk minimisation activities e g labelling changes. communications with prescribers or other steps,2 8 Periodicity and PBRER data lock point. 2 8 1 International birth date and data lock point. Each medicinal product should have an IBD the IBD is the date of the first marketing approval for any. product containing the active substance granted to any company in any country in the world When a. report contains information on different dosage forms formulations or uses indications routes and or. populations the date of the first marketing approval for any of the various authorisations should be. regarded as the IBD and therefore determine the DLP for purposes of the PBRER The DLP is the date. designated as the cut off for data to be included in a PBRER Through PBRERs prepared with. harmonised DLPs based on a common IBD the same updated safety and benefit risk information can. be reviewed globally by different regulatory authorities. When a separate PBRER is prepared for a fixed dose combination product see Section 2 2 the DLP. for that PBRER can be based on either the earliest IBD of one of the component active substances or. the IBD of the first marketing approval anywhere in the world for the fixed dose combination. When clinical development of a medicinal product continues following marketing approval if desired by. the sponsor MAH the beginning of the DSUR reporting interval can be synchronized with the IBD. based cycle so that both the DSUR and PBRER can be prepared at the same time using the same DLP. This approach will facilitate use of the proposed common sections modules for both the PBRER and. DSUR when both are submitted annually see Appendix D. 2 8 2 Managing different frequencies of PBRER submission. The need for the submission of a PBRER and the frequency of report submission to regulatory. authorities are subject to national or regional regulatory requirements and usually depend on such. factors as approval dates the length of time the product has been on the market and the extent of. knowledge of the benefit risk profile of the product The PBRER format and content are intended to. apply to periodic reports that cover reporting periods of 6 months or longer Once a drug has been. marketed for several years national or regional regulation may allow the frequency of submission to. be extended to longer time intervals e g greater than one year for products considered to have an. established and acceptable profile or considered to be low risk however more frequent PBRERs may. continue to be required in other regions As a result the following scenarios may be encountered by. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 10 45, PBRERs may be required on 6 monthly annual and less frequent submission timetables. simultaneously across different regions, Changes in reporting frequency may also apply after important additions or changes in clinical use. are approved e g new indication s and or new population s In these circumstances it is. possible that the reporting interval will be shortened even for older products with a previously. reduced frequency of PBRER submission, An ad hoc PBRER may be requested by a regulatory authority see Section 2 8 2 1 of this. Independent of the length of the interval covered by the report. Each PBRER should be stand alone and reflect new and cumulative information currently available. to the MAH, Regulators will normally accept use of the IBD to determine the DLP for PBRERs Where national. or regional requirements differ from this the MAH may wish to discuss with the relevant regulatory. authority Use of a single harmonised IBD and DLP for each product is important in order to reduce. the burden of work involved in preparing PBRERs and respects the original purpose of the PBRER. to prepare a single worldwide summary on a product that can be submitted to different regulatory. authorities, For newly approved products a 6 monthly periodicity applies in many regions for at least the first. 2 years after approval, For PBRERs submitted on a routine regular basis the reports should be based on cumulative data. with interval data sets of 6 months or multiples thereof. Sections that provide interval information are likely to need to be updated for each PBRER and the. content used in the previous PBRER can be reviewed and reused for sections where no new. information has arisen since preparation of the last PBRER if appropriate Following review it may. be determined that sections providing evaluation of cumulative data may not need to be updated if. the content remains up to date with current information See Figure 1. In situations when an MAH is preparing PBRERs on both a six monthly and annual basis for. different regulatory authorities the regulatory authority requiring a PBRER on a six month cycle. may accept PBRERs containing 12 month interval data See Figure 2 MAHs should discuss the. acceptability of this approach with the relevant regulatory authority ies. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 11 45, Figure 1 Submission of PBRERs Based on the Same Data Lock Point with Various Reporting. Shading indicates period of interval data, For all reports the cumulative data reflect all data from the IBD DIBD. IBD Data Lock Point,Region A 6 months,cumulative,Region B 12 months data are. Region C longer, Region D ad hoc PBRERs ongoing in other regions interval specified in request. Region E ad hoc PBRER not prepared for other regions. time years 0 1 2 3, update the most recent cumulative and interval data as appropriate. Cumulative Clinical Trial Summary Tabulation of Serious Adverse Events Clinical Trial Exposure data only. Figure 2 Submission of 6 Month and Annual PBRERs,6 month PBRER A C. Annual PBRER B D,Month 0 6 12 18 24, Region 1 requires 6 monthly PBRER and receives PBRER A B C and D assuming agreement has been. reached with pertinent regulatory authority ies, Region 2 requires annual PBRER and receives PBRER B and D. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 12 45,2 8 2 1 Ad hoc for cause PBRERs. Ad hoc PBRERs are reports outside the routine reporting requirements and may be requested by some. regulatory authorities Where an ad hoc report is requested and a PBRER has not been prepared for a. number of years it is likely that a completely new report will need to be prepared by the MAH. 2 8 3 Time interval between data lock point and the submission. As a result of the expanded scope of the PBRER the time interval between the DLP and submission of. PBRERs should be as follows, PBRERs covering intervals of 6 or 12 months within 70 calendar days. PBRERs covering intervals in excess of 12 months within 90 calendar days. ad hoc PBRERs 90 calendar days unless otherwise specified in the ad hoc request. The day of DLP is day 0 of the 70 or 90 calendar day interval between the DLP and report submission. Where national or regional requirements differ from the above the MAH should discuss the timeline for. submission with the relevant regulatory authority,2 9 Format and presentation of PBRER. 2 9 1 Format, The recommended format and content of the PBRER including table of contents section numbering. and content of each section is outlined below, The full ICH Guideline E2C R2 format should be used for all PBRERs When no relevant information is. available or a PBRER section is not applicable this should be stated Particular sections of the PBRER. may share content with other regulatory reports e g documents described in ICH guidelines E2E and. E2F It may be possible for the MAHs to take advantage of the modular approach of the PBRER i e. sections that can be separated and submitted independently or combined with other documents to. facilitate such regulatory needs maximize the utility of the content and reduce duplicate work. 2 9 2 Presentation, The recommended table of contents including section numbering for the PBRER is provided below. Title Page,Executive Summary,Table of Contents,1 Introduction. 2 Worldwide Marketing Approval 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. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 13 45, 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 Period. 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. 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 Summary 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 Effectiveness Information. 17 2 Newly Identified information on Efficacy Effectiveness. 17 3 Characterisation of Benefits, 18 Integrated Benefit Risk Analysis for Approved Indications. 18 1 Benefit Risk Context Medical Need and Important Alternatives. 18 2 Benefit Risk Analysis Evaluation,19 Conclusions and Actions. 20 Appendices,3 Guidance on contents of the PBRER, All sections should be completed and when no information is available this should be stated Note. that Section 3 N of this guideline provides guidance on the content of Section N of the PBRER For. example Reference Information described in Section 3 6 1 of this guideline corresponds to Section. 6 1 of the PBRER,Title Page, The title page of the PBRER should include the following information. Date of the report,Medicinal product s, ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER. EMA CHMP ICH 544553 1998 Page 14 45,Reporting interval. MAH s name s and address es and, Any statement on the confidentiality of the information included in the PBRER. Executive summary, This section should provide a concise summary of the most important information contained in the. The following information should be included in the Executive Summary. Introduction,Reporting interval, Medicinal product s mode s of action therapeutic class es indication s dose s route s of. administration formulation s, Estimated cumulative exposure of clinical trial subjects interval and cumulative post approval. Number of countries in which the medicinal product is approved. Summary of overall benefit risk evaluation based on Section 18 2 of the PBRER. Actions taken or proposed for safety reasons e g significant changes to the reference product. information other risk minimisation activities and. Conclusions,Table of Contents,3 1 Introduction,Section 1 of the PBRER should include. reporting interval, medicinal product s mode s of action therapeutic class es dose s route s of. administration formulation s, a brief description of the approved indication s and population s. a brief description and explanation of any information that has not been included in the PBRER. the rationale for submission of multiple PBRERs for the medicinal product if applicable. 3 2 Worldwide marketing approval status, Section 2 of the PBRER should provide a brief narrative overview including date of first approval. indication s approved dose s and where approved if applicable. ICH guideline E2C R2 on periodic benefit risk evaluation report PBRER.