Periodic Benefit Risk Evaluation Report (PBRER)

The Periodic Benefit Risk Assessment Report (PBRER) is a standard for periodic benefit-risk evaluation reporting on marketed products (including approved drugs that are under further study) among the ICH regions.

When a medicinal product is approved for marketing, demonstration of safety and efficacy are generally based on data from a limited number of patients, with many studied under the controlled conditions of randomized trials. Higher risk subgroups and patients with concomitant illnesses that require use of other drugs are often excluded from clinical trials, and long-term treatment data is 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 so on), and events too rare to occur in clinical trials (such as severe liver injury) may be observed.

These factors underlie the need for continuing analysis of relevant safety, efficacy, and effectiveness information throughout the lifecycle of a medicinal product promptly and periodically, for an overall assessment of the accumulating data.

The PSUR provides a comprehensive picture of the safety of approved medicinal products, as the assessment of the risk of a medicinal product is most meaningful when considering its benefits. The PBRER provides greater emphasis on benefits, particularly when risk estimates change, and places greater emphasis on the cumulative knowledge regarding a medicinal product, while retaining a focus on new information.

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.

 PBRER Format (Based on ICH-E2C R2 Guideline)

The recommended table of contents, including section numbering, for the PBRER is provided below:

Title Page

The title page of the PBRER should include the following information:

1. Date of the report
2. Medicinal product(s)-Name of medicinal product/fixed dose combination
3. IBD-The marketing authorization date of the medicinal product of which report is being written.
4. Reporting interval-Periodicity covering the duration of review period. For example: Reporting interval for an Annual PBRER is 12-May-2019 to 11-May-2020 (11-May-2020 is the Data Lock Point for this PBRER)
5. MAH(s) name(s) and address(es): Name of the pharma company/sponsor and address need to be included.
6. Any statement on the confidentiality of the information included in the PBRER

Executive Summary

A concise summary of the most important information contained in PBRER

• 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 exposure
• 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 minimization activities)
• Conclusions

Table of Contents

(Click on each section/sub-section for detailed description with examples)

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

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

9.1 Other Clinical Trials

9.2 Medication Errors

10. Nonclinical 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 Characterization of Risks

16.5 Effectiveness of Risk Minimization

17. Benefit Evaluation

17.1 Important Baseline Efficacy/Effectiveness Information

17.2 Newly Identified Information on Efficacy/Effectiveness

17.3 Characterization 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

1. Introduction

A brief introduction needed which should contain the following information.

• IBD: Include the date when sponsor received approval for marketing the medicinal product.
• Reporting interval: Periodicity covering the duration of review period needs to be included
• Medicinal product(s) information pertaining to mechanism of action, therapeutic class, dose(s), route(s) of administration and formulation.
• 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

2. Worldwide Marketing Approval Status

A brief narrative overview including date of first approval for marketing authorization, launch dates indication(s), approved dose(s), strength(s) and the country where it is approved.

If there are multiple products in different countries with different approval dates or launch dates and approved indications. Information could be presented in a tabular format as below:

3. Actions Taken in the Reporting Interval for Safety Reasons

A brief description of significant actions related to safety that have been taken during the reporting interval, related to either investigational uses or marketing experience by the MAH, sponsor of a clinical trial(s), regulatory authorities, data monitoring committees, or ethics committees should be presented in this section.

Possible actions related to investigational drugs:

Refusal to authorize a clinical trial for ethical or safety reasons

• Partial 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 approval for a tested indication, including voluntary withdrawal of a marketing application
• Risk management activities, including:
• Protocol modifications because of 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 o Plans for new studies to address safety concerns

Possible actions related to marketed drugs:

• Failure to obtain or apply for a marketing approval renewal
• Withdrawal or suspension of a marketing approval
• Suspension of supply by the MAH
• Risk management activities, including:
• Significant restrictions on distribution or introduction of other risk minimization measures
• Significant safety-related changes in labelling documents that could affect the development program, including restrictions on use or population treated
• Communications to healthcare professionals o New post marketing study requirement(s) imposed by regulator(s).

If there were no clinical trials or no actions taken pertaining to the medicinal product’s safety. Below statements might be presented in this section.

Actions related to investigational uses:

During the reporting interval, no clinical trial was initiated, conducted, or finalized by the company; therefore, this section is not applicable.

Actions related to marketing experience:

No actions due to safety reasons have been initiated related to <<Medicinal product name>>

4. Changes to Reference Safety Information

This section should list any significant changes made to the reference safety information pertaining to the safety of medicinal product within the reporting interval.

Possible changes related to safety update(s) in the following sections

• Contraindications
• Warnings
• Precautions,
• Adverse drug reactions (ADRs)
• Overdose, Drug Interactions
• Important findings from ongoing and completed clinical trials and significant non-clinical findings (e.g., Hepatotoxicity, carcinogenicity studies).

A clean version of the current reference safety information (RSI) document that is used at the DLP of the PBRER should be included in Appendix 1

Example:

If any new adverse reactions identified from spontaneous reporting sources and added to the RSI during the reporting interval, the following sentence might be appropriate to include.

The following two adverse reactions have been identified during post-approval use of <<Medicinal product name>>. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous system disorders: tremor

Psychiatric disorders: confusion, worsening aggression

5. Estimated Exposure and Use Patterns

This section provides the estimates of the size and nature of the population exposed to the medicinal product cumulatively and during the reporting interval time. A brief description of the method used for calculating the exposure data need to be included.

5.1 Cumulative Subject Exposure in Clinical Trials

Following information need to be presented (as required)

• 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 recognized that for older products, precise data might not be available. (i.e., for established/mature products, this data is not required to present, since it difficult to track the precise data).
• Presentation of cumulative subject exposure data in clinical trials. Stratifying the data based on age, age group, 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 duration of exposure between subjects randomised to the investigational medicinal product or comparator(s), or disparities in duration 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 (SAEs) 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.

Example:

Cumulatively there were three (03) clinical trials completed. The exposure data of <<Medicinal product name>> in these three (03) studies is given in the below table.

Cumulatively 141 patients were exposed to <<Medicinal product name>> in clinical trials.

Cumulative subject exposure in clinical trials

5.2 Cumulative and Interval Patient Exposure from Marketing Experience

For the post-marketing exposure, separate estimations need to be presented in this section for cumulative period and reporting interval period with the brief explanation of the method used for exposure calculation. The comprises the following three sub-sections:

1. 1. Post-approval (non-clinical trial) exposure
   2. Post-approval use in special populations
   3. Other post-approval use

1. Post-approval (non-clinical trial) exposure:

An overall estimation of patient exposure should be provided. In addition, the data should be routinely presented by indication, sex, age, 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

Example:

The estimated exposure data are derived from quantities of <<Medicinal product name>> sold and remain an approximation of the total quantity of <Medicinal product name>> sales during the reporting interval covered by this report, <<Reporting Interval>>.

Cumulative patient exposure to <<Medicinal product name>>

Method used for exposure calculation:

The total number of volumes sold was XX,XXX packages and total number of volumes sold in mg was XX,XXX,XXX.

WHO defined daily dose (DDD) for <<medicinal product>> is XX mg/day.

The total number of exposure units represented by DDDs sold since the IBD is estimated to be XXX,XXX patient treatment days.

2. Post-approval use in special populations:

Where post-approval 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 include non-interventional studies designed to obtain this information, including registries. 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); and
• Patients of different racial and/or ethnic origins

Example:

The accurate data pertaining to special population exposure is not available. However, an analysis of the number of cases received for special populations is done below:

Exposure during pregnancy:

Cumulatively there were four (04) non-serious cases (“Case ID can be included”) of <<Medicinal product>> exposure during pregnancy. Of the 4 cases, three (3) were spontaneous and one was a solicited case. The preferred terms included hypertension, myalgia, fatigue, vomiting, maternal exposure before pregnancy, exposure during pregnancy and pregnancy.

All the four (4) pregnant subjects (age range: 20 to 35 years) were exposed to <<Medicinal product>> in an unknown trimester. In the 4 cases, patient’s medical history and concomitant medications were not reported, and the pregnancy outcome was unknown.

No special trends were observed in these pregnancy cases. The RSI does not recommend the use of <<Medicinal product>> during pregnancy and in women of childbearing potential not using contraception. There is no new information which should warrant an update to the current approved RSI.

Paediatric population:

During the reporting interval the company received XX cases with the use of <<Medicinal product>> in paediatric population containing XXX AEs (serious unlisted XX, serious listed XX, non-serious unlisted XX and non-serious listed XX). Cumulatively, the MAH received XXX cases containing XXX AEs (serious unlisted XXX, serious listed XX, non-serious unlisted XXX and non-serious listed XXX).

Elderly population:

During the reporting interval there are XXX elderly cases reported. In which XXX cases were serious and XXX cases were non-serious. The gender distribution was: male (XXX), female (XXX) and Unknown (XX). The country of origin was USA (XXX) and Japan (XX). The sources of information were Spontaneous (XXX) and solicited (XX). There is no trend or pattern in the AEs reported among elderly population in comparison with the adult population.

3. Other post-approval use

If the MAH becomes aware of patterns of use of the medicinal product considered relevant for the interpretation of safety data, provide a brief description thereof.

Examples of such patterns of use may include overdose, drug abuse, misuse, and use beyond that recommended in the reference product information (e.g., an anti-epileptic drug used for neuropathic pain and/or prophylaxis of migraine headaches). Such patterns may be regional. If known, the MAH may briefly comment on whether use beyond that recommended in the reference product information is supported by clinical guidelines, clinical trial evidence, or an absence of approved alternative treatments. Quantitative use information should be provided, if available. For purposes of identifying patterns of use outside the terms of the reference product information, the MAH should use the appropriate sections of the reference product information that was in effect at the DLP of the PBRER (e.g., approved indication, contraindications).

6. Data in Summary Tabulations

This section comprises cumulative summary tabulations of SAEs from clinical trials and post‑marketing sources that have been reported to the MAH since the DIBD.

6.1 Reference Information: Need to specify the current version of RSI used for preparation of the report and current version of MedDRA used for the analysis of adverse reactions from the safety database.

6.2 Cumulative Summary Tabulations of Serious Adverse Events from Clinical Trials:

It includes the cumulative summary tabulation of SAEs reported in the MAH’s clinical trials, from the DIBD to the DLP of the current PBRER. The MAH 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 organized by system organ class (SOC), for the investigational drug, as well as for the comparator arm(s) (active comparators, placebo) used in the clinical development program. Data can be integrated across the program. Alternatively, when useful and feasible, tabulations of SAEs can be presented by trial, indication, route of administration, or other variables. This section should not serve to provide analyses or conclusions based on the SAEs.

The following points needs to be considered while presenting SAE information from clinical trials in the summary tabulations.

• Only Serious adverse events (SAEs) from clinical trials are needed to include in the tabulations. Non serious events are not required to include.
• When the MedDRA terminology is used for coding the adverse event/reaction terms, the Preferred Term level and SOC should be presented in the summary tabulations.
• The tabulations should include blinded and unblinded clinical trial data. Unblinded SAEs might originate from completed trials and individual cases that have been unblinded for safety-related reasons (e.g., expedited reporting), if applicable. Sponsors/MAHs should not unblind data for the specific purpose of preparing the PBRER.
• Exclusion of Protocol exempted events and study endpoints from the tabulations: Certain adverse events in clinical trials 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).
• Causality assessment is generally useful for the evaluation of individual rare ADRs. 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 SAEs for the investigational drug, active controls, and placebo. It may be useful to give rates by dose

Example:

A cumulative (IBD to DLP) summary tabulation of serious adverse events (SAE) from Company-sponsored clinical trials is provided below. The SAEs presented in this summary tabulation were derived from Company-sponsored interventional clinical trials.

6.3 Cumulative and Interval Summary Tabulations from Post marketing Data Sources

This section comprises both “cumulative” and “interval” summary tabulations of adverse reactions, from the IBD to the DLP of the current PBRER.

‘Related’ causality for adverse events from Spontaneous sources: As described in the ICH E2D guidance, spontaneously reported adverse events for the marketed medicinal products usually imply at least a suspicion of causality by the reporter and should be considered to be adverse reactions for regulatory reporting purposes.

The summary tabulation should include:

• Both serious and non serious adverse drug reactions from spontaneous ICSRs, which includes reports from healthcare professionals, consumers, scientific literature, and regulatory authorities
• Serious adverse reactions from non-interventional studies
• Serious adverse reactions from other solicited reports

The tabulation should be organized by SOC by including both interval and cumulative data presented side-by-side.

For special issues or concerns, additional tabulations of adverse reactions can be presented by indication, route of administration, or other variables. This section should not serve to provide analyses or conclusions based on the data presented.

Example:

During the reporting interval the Marketing authorization holder received XXXX adverse events from XXX case reports: XXXX serious adverse events and XXXX non-serious adverse events worldwide associated with company’s medicinal products.

7. Summaries of Significant Findings from Clinical Trials during the Reporting Period

This section provides a brief summary of clinically important emerging efficacy/effectiveness and safety findings obtained from the company sponsored clinical trials that have become available during the reporting interval of the report. The safety signals arising from clinical trial sources should be tabulated in section 15 of the PBRER. Evaluation of the signals (whether or not categorized as refuted signals or either potential risks or identified risks) that were closed during the reporting interval should be presented in Section 16.2 of the PBRER. 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 characterized in sections 16.3 and 16.4, respectively. Findings from clinical trials not sponsored by the MAH should be described in the relevant sections of the PBRER. When relevant to the benefit-risk evaluation, information on lack of efficacy from clinical trials for treatments of non-life-threatening diseases in approved indications should also be summarized in this section.

Information on lack of efficacy from clinical trials with products intended to treat or prevent serious or life-threatening illnesses should be summarized in section 13 of the PBRER.

When possible and relevant, data categorized by sex and age (particularly children versus adult), indication, dose, and region should be presented. A listing of any MAH-sponsored post marketing interventional trials with the primary aim of identifying, characterizing, or quantifying a safety hazard, or confirming the safety profile of the medicinal product that were completed or ongoing during the reporting interval should be included in an appendix. The listing should include the following information for each trial:

• Study identification (e.g., protocol number or other identifier)
• Study title (abbreviated study title, if applicable)
• Study type (e.g., randomized 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 MAH) and projected completion dates
• Status:

1. Ongoing (clinical trial has begun)
2. Completed (clinical study report is finalized)

7.1 Completed Clinical Trials: This sub-section includes 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 synopsis. It could include information that supports or refutes previously identified safety concerns, as well as evidence of new safety signals.

7.2 Ongoing Clinical Trials: This sub-section includes a brief summary of the 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). It could include information that supports or refutes previously identified safety concerns, as well as evidence of new safety signals.

7.3 Long-Term Follow-up: This sub-section includes information from long-term follow-up of subjects from clinical trials of investigational drugs, particularly advanced therapy products

7.4 Other Therapeutic Use of Medicinal Product: This sub-section includes clinically important safety information from other programs conducted by the MAH that follow a specific protocol, with solicited reporting as per the ICH E2D guidance (e.g., expanded access programs, compassionate use programs, particular patient use, single-patient investigational new drug applications (INDs), treatment INDs, and other organized data collection).

7.5 New Safety Data Related to Fixed Combination Therapies: This sub-section includes important safety information pertaining to combination therapies.

If the product for which PBRER is being written is also approved or under development as a component of a fixed combination product or a multi drug regimen.

If this PBRER is for a fixed combination product, this section should summarize important safety information arising from the individual components. The information specific to the combination can be incorporated into a separate section(s) of the PBRER for one or all of the individual components of the combination.

Example:

The clinical trial study information (completed/ongoing/long term follow ups) can be presented in the below format:

Study Number: XXXXXXXX

Study Title: A double-blind, randomized, placebo-controlled, parallel-group XXXXXXXX

Summary: This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted worldwide. The primary objective of the study was to qualify the XXXXX<<Provide the concise summary of study which included study method, results, SAE information outcome etc.,>>

Note: This section/sub section would be ‘not applicable’ if there were no completed/ongoing and long term follow up studies for the medicinal product and it is used only as monotherapy and not part of any combination therapies. The below statements might be added in such instances.

“No clinical trials were completed during the reporting period.”

“There were no ongoing company-sponsored interventional clinical trials for <<medicinal product name>> during this reporting periods.”

 “No long-term follow-up studies were conducted for <<medicinal product name>> during the reporting period.”

“There were no other programs conducted with <<medicinal product name>> which followed a specific protocol during the reporting period”

“This section is not applicable as <<medicinal product name>> is monotherapy and is not marketed as a combination drug.”

8. Findings from Non-Interventional Studies

This section summarizes the relevant safety information that could have potential impact on the benefit-risk evaluations which could obtained from non-interventional studies sponsored by MAH and that have become available during the reporting interval (e.g., observational studies, epidemiological studies, registries, and active surveillance programs). This should include relevant information from drug use studies when applicable to multiple regions.

A listing of any MAH-sponsored, post marketing non-interventional study or studies with the primary aim of identifying, characterizing, or quantifying a safety hazard; confirming the safety profile of the medicinal product; or measuring the effectiveness of risk management measures that were completed or ongoing during the reporting interval should be included in an appendix (see section III.G (3.7) of this guidance 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 report where stipulated by regional requirements.

Example:

If there is significant safety information available from a company sponsored non-interventional studies having potential impact on the benefit risk assessment, the details can be presented in tabular format or can be summarised as described above in previous section.

If there were no non-interventional studies initiated, conducted, completed for the <<medicinal product name>>the below statement can be included.

“The company did not initiate, conduct, complete or report any non-interventional studies with <<medicinal product>> products during the reporting interval of this PSUR.”

9. Information from Other Clinical Trials and Sources

9.1 Other Clinical Trials: This subsection summarizes the information accessible to the MAH with reasonable and appropriate effort from any other clinical trial/study sources, including results from pooled analyses or meta-analyses of randomized clinical trials, and safety information provided by co-development partners or from investigator-initiated trials.

Note: If no information is available, below statement could be included for this subsection.

“No information from other clinical trials/ study sources is accessible to the company.”

9.2 Medication Errors: This subsection summarizes 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 might or might not involve a patient. Such information could be relevant to the interpretation of safety data or the overall benefit-risk evaluation of the medicinal product. A medication error can arise at any stage in the medication use process, and can involve patients, consumers, or healthcare professionals. This information can be received by the MAH via spontaneous reporting systems, medical information queries, customer complaints, screening of digital media, patient support programs, or other available information sources. Signals or risks identified from any information source and/or category of reports should be presented and evaluated in the relevant section of the PBRER.

Example:

The global safety database needs to be searched for ICSRs with any reported medication errors and associated events. It can be searched either with High Level Group Term (HLGT) Medication Errors or with Preferred Terms (PTs) such drug administration error, treatment noncompliance, prescribed overdose, drug dose omission, incorrect dose administered, drug prescribing error, inappropriate schedule of drug administration etc.,

Summaries of ICSR case reports with serious/Fatal/LT events associated with medication errors needs to be presented in a concise manner.

Brief summary of all the cases could be presented in a tabular format like below:

10. Nonclinical Data

This section summarizes major safety findings from nonclinical in vivo and in vitro studies (e.g., carcinogenicity, reproduction, or immunotoxicity studies) ongoing or completed during the reporting interval. Results from studies designed to address specific safety concerns should be included in the PBRER, regardless of the outcome. Implications of the findings presented in PBRER section 10 should be discussed in the relevant evaluation sections of the report.

Example:

Similar to the information presented in the clinical study section, the significant safety findings of the non-clinical studies need to be presented like below:

STUDY NUMBER

Study Title: A Developmental and Perinatal/Postnatal Reproduction Study of XXXX by Oral BID Administration in Rats, Including a Postnatal Behavioral/Functional Evaluation

Study Type: Toxicokinetic study

Sample size: XXX rats

Study objectives: The objectives of this study was to detect potential adverse effects of XXXX (a major human metabolite of <<medicinal product>>.) on Crl: CD(SD) rat and development of the offspring consequent to exposure of the F0 generation female from implantation through lactation and weaning.

Results: There were no test article-related deaths. One F0 generation female rat in the control group was euthanized due to a snout injury on DG 10. (Continues…)

Note: If there were no non-clinical studies were conducted pertaining to this <<medicinal product>>. Below statement might be used.

“No non-clinical studies were initiated or ongoing concerning <<medicinal product>> during the reporting period.”

11. Literature

This section summarizes new and significant safety findings, either published in the peer-reviewed scientific literature or made available as unpublished manuscripts, relevant to the approved medicinal product that the MAH has become aware of during the reporting interval. Literature searches for PBRERs should be wider than those for individual adverse reaction cases, and include studies reporting safety outcomes in groups of subjects. If relevant, information on active substances of the same class should be considered.

Example:

Literature searches were conducted to identify significant safety findings associated with <<medicinal product>>, published in scientific literature during the reporting period of <<Reporting Interval>> using the databases MEDLINE and EMBASE.

Abstracts/Articles of interest containing significant safety information are summarized and presented below.

Article Title:

Antihypertensive medications and the risk of kidney stones in older adults: a retrospective cohort study. Hypertension research: official journal of the Japanese Society of Hypertension

Summarized Abstract/Article:

Alexander, R Todd, McArthur, et al. conducted a retrospective, population-based cohort study using linked health administrative databases to assess the impact of different classes of antihypertensives on the risk of kidney stone (Continues…)

Medical/Company comment: The safety topic of kidney stones associated with Calcium channel blockers is not well documented in the current RSI of the medicinal product (continues…)

12. Other Periodic Reports

Unless otherwise specified by national or regional regulatory requirements, the MAH should prepare a single PBRER for a single active substance. However, if an MAH prepares multiple PBRERs for a single active substance (e.g., covering different indications, or formulations), section 12 should summarize significant findings from the other periodic reports if they are not presented elsewhere within this report. When available, based on contractual agreements, the MAH should summarize significant findings from periodic reports provided during the reporting interval by other parties (e.g., sponsors, MAHs, other contractual partners).

The significant safety findings from other PBRER reports of the same medicinal product is presented here. If there were no other reports, the following statement might be used.

“No other relevant periodic reports have been written during the reporting period for <<medicinal product>>  during the reporting period.”

13. Lack of Efficacy in Controlled Clinical Trials

The significant safety information pertaining to the lack of drug efficacy of the medicinal product which is intended to treat or prevent serious or life-threatening illnesses (e.g., excess cardiovascular adverse events in a trial of a new anti-platelet drug for acute coronary syndromes) could reflect a significant risk to the treated population and should be summarized in section.

From the company-sponsored clinical trials, if there are significant safety findings of lack of drug efficacy, the information can be presented similar to example given in section 7. If there were no company sponsored clinical trails for monitoring the efficacy of medicinal product the following statement might be used.

“No company-sponsored controlled clinical trial monitoring efficacy was ongoing or completed during the reporting interval.”

14. Late-Breaking Information

This section includes summarized information on potentially important safety and efficacy/effectiveness findings that arise ‘after the DLP but while the PBRER is in preparation’. Examples include clinically significant new publications; important follow-up data; clinically relevant toxicological findings; and any action that the MAH, a data monitoring committee, or a regulatory authority has taken for safety reasons. New individual case reports should not be included unless they are considered to constitute an important index case (i.e., the first instance of an important event), an important safety signal, or where they may add information to the evaluation of safety concerns already presented in the PBRER (e.g., a well-documented and unconfounded case report of aplastic anaemia in a medicinal product known to be associated with adverse effects on the bone marrow). Any significant change proposed to the reference product information that has occurred after the DLP of the report but before submission should also be included in this section, where feasible. Such changes could include a new contraindication, warning/precaution, or new adverse drug reaction. The data presented in this section should also be taken into account in the evaluation of risks and new information.

Example:

After the data lock point of this report, an amendment has been made to the reference safety information CCDS v3.0 dated XX XXX XXXX. The CCDS v4.0 dated XX XXX XXXX was approved with an update to the warnings regarding dose titration, as detailed below:

Section 6.0 WARNINGS AND PRECAUTIONS:

The dose of <<medicinal product>> should be titrated to determine the most appropriate dose for each patient. When first prescribed, therapy with <<medicinal product>> should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is well tolerated. If the adverse effect does not resolve or decrease, consideration should be given to discontinuing <<medicinal product>>.

Once a stable dose has been achieved, treatment should be reassessed periodically in the context of the patient’s underlying condition and their concomitant medications.

The above amendment was implemented to align with the <<health authority>> recommendation.

Note: If there was no significant information after DLP and before submission of report, below statement might be added for this section.

“There were no potentially important safety, efficacy and effectiveness findings that arose during the preparation of this report after the DLP.”

15. Overview of Signals: New, Ongoing, or Closed

This section comprises a high-level overview of safety signals that were closed (i.e., the evaluation was completed) during the reporting interval as well as ongoing signals that were undergoing evaluation, at the end of reporting interval.

For the purposes of the PBRER, 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 MAH. It should be noted that a safety signal is not synonymous with a statistic of disproportionate reporting for a specific drug/event combination because a validation step is called for. Signals can be qualitative (e.g., a pivotal individual safety case report, case series) or quantitative (e.g., a disproportionality score, findings of a clinical trial or epidemiological study). Signals can arise in the form of an information request or inquiry on a safety issue from a regulatory authority. Decisions regarding the subsequent classification of these signals and the conclusions of the evaluation involve medical judgment and scientific interpretation of available data, which is presented in section 16 of the PBRER. A new signal is a signal that the MAH has become aware of during the reporting interval. New clinically important information on a previously closed signal* that has become available during the reporting period of the PBRER (i.e., a new aspect of a previously refuted signal or recognized risk likely to warrant further action to verify) would also constitute a new signal. New signals can be classified as closed or ongoing, depending on the status of signal evaluation at the DLP of the PBRER. Examples would include new information on a previously:

• Closed and refuted signal, which would result in the signal being reopened
• Identified risk that is indicative of a clinically significant difference in the severity of the risk (e.g., transient liver enzyme increases are identified risks, and new information is received indicative of a more severe outcome such as hepatic failure; neutropenia is an identified risk and a well-documented and unconfounded case report of agranulocytosis is received)
• Identified risk for which a higher frequency of the risk is newly found (e.g., in a subpopulation)
• Potential risk that, if confirmed, would warrant a new warning, precaution, new contraindication or restriction in indication(s) or population, or other risk minimization activities

Within this section or as an appendix, a tabular listing of all signals, ongoing or closed, at the DLP of the PBRER should be included. This table should include the following information

• A brief description of the signal
• Date when the MAH became aware of the signal
• Status of the signal (closed or ongoing at the DLP)
• Date when the signal was closed, if applicable
• Source of the signal
• A brief summary of key data
• Plans for further evaluation
• Actions taken or planned

Detailed signal evaluations for closed signals should not be included in this section, but instead should be presented in section 16.2 (Signal Evaluation) of the PBRER. Evaluation of new information in relation to any previously known identified and potential risks and not considered to constitute a newly identified signal should be provided in section 16.3 (Evaluation of Risks and New Information) of the PBRER. When a regulatory authority has requested that a specific topic (not considered a signal) be monitored and reported in a PBRER, the MAH should summarize the result of the analysis in PBRER section 15 if it is negative. If the specific topic becomes a signal, it should instead be included in the signal tabulation and discussed in PBRER section 16.2.

Example:

An overview of new, ongoing, and closed signals at the end of reporting interval is listed in the below table.

Apart from the high-level overview on signals, The following safety topics (if applicable) which are considered as ‘non-validated signals’ can be discussed in this section:

• Safety topics requested by health authority in previous PSUR for special monitoring.
• Safety topics agreed for routine pharmacovigilance activities by MAH in the previous PSUR.
• Targeted medical events, which are the events of specific interest that are medically important, with a known health risk associated with company’s medicinal product.

16. Signal and Risk Evaluation

This section includes the evaluation of all signals closed during the reporting interval, evaluation of new information with respect to previously recognized identified and potential risks, an updated characterization of important potential and identified risks, where applicable and a summary of the effectiveness of risk minimization activities in any country or region that might have utility in other countries or regions.

The evaluation subsections should not summarize or repeat information presented in previous sections of the PBRER, but should instead provide an interpretation of the information, with a view towards characterizing the profile of those risks assessed as important. As a general rule, it is not necessary to include individual case narratives in the evaluation sections of the PBRER; however, when 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.

16.1 Summary of Safety Concerns:

This subsection provides a succinct summary of safety concerns which comprises of following:

1. Important Identified risks
2. Important Potential risks and
3. Important Missing information

at the beginning of the reporting interval covered by the report.

The following factors should be considered when determining whether or not a risk is important:

• 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)
• Potential for avoidance of a medical product with a preventive benefit as a result of public perception of risk

For products with an existing safety specification (Risk management plan, RMP): This section can be either the same as, or be derived from, the safety specification summary (according to the ICH E2E guidance) at the start of the reporting interval of the current PBRER.

For products with No safety specification (Risk management plan, RMP): This section should provide information on the important identified and potential risks and important missing information associated with use of the product, based on pre-approval and post-approval 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
• Pharmacological class effects

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

Example:

Find the below some examples for the summary of safety concerns presented in table:

16.2 Signal Evaluation:

This subsection summarizes 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. Therefore, the two main categories that should be included in this section are:

1. Those signals that, following evaluation, have been refuted as false signals based on medical judgment and a scientific evaluation of the currently available information
2. Those signals that, following evaluation, have been categorized 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 to provide to the regulatory authorities the basis upon which the signal was either refuted or considered to be a potential or identified risk by the MAH. It is recommended that the level of detail provided in the description of the signal evaluation be proportionate to the medical significance of the signal, its public health importance, and the extent of the available evidence. When multiple evaluations are included under both categories of closed signals, they can be presented in the following order:

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

Where applicable, the closed signal evaluations can be presented by indication or population.

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

• Source 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) or Standardized 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 ICSR (e.g., an index case of well-documented agranulocytosis or Stevens Johnson syndrome)
• Discussion
• Conclusion

Example:

This subsection is the heart of PBRER which provides the new significant safety information for the medicinal product in the current reporting interval.

Robust analysis of cases with new safety concerns (signals) would be performed in this section.

A brief framework for stratification of cases outlined below before performing the case-wise analysis.

Depression/suicidality related cases

Search criteria (For Retrieving the cases with this safety signal from safety database)

A standardised MedDRA Query (SMQ) for depression and Sucidality PTs (Suicide attempt, depression suicidal, completed suicide etc.,) were applied for pulling the line listing of cases containing the desired PTs from the safety database.

Discussion

Cumulatively, the company received XX cases from European countries (Spain, Portugal, Italy, Germany, and U.K.) under the preferred terms Depression (XX), Suicidal ideation (XX), Suicide attempt (XX), and Completed suicide (XX).

Grouping based on demographics:

Mean age: 58.5

Case Wise Analysis of Depression/suicidality related cases

A clear and well detailed summarization of cases narratives need to be presented here for causality assessment followed by discussion and conclusion.

 16.3 Evaluation of Risks and New Information

This subsection provides a critical appraisal of new information relevant to previously recognized risks that is not already included in section 16.2 of the PBRER, Signal Evaluation. New information that constitutes a signal with respect to a previously recognized risk or previously refuted signal should be presented in the tabular summary of signals (in 16.1 section) and evaluated in section 16.2 of the PBRER, if the signal is also closed during the interval of the PBRER.

Updated information on a previously recognized risk that does not constitute a signal should be included in this section.

Examples include information that confirms a potential risk as an identified risk, or information that allows further characterization of a previously recognized risk.

New information can be organized as follows:

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

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

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

 Example:

Let us take “Parkinsonism” as an important potential risk, which could be evaluated as below:

Important Potential Risk: Parkinsonism

Search PT terms: Parkinsonism, Bradykinesia

(Based on these search terms, relevant cases would be retrieved from the safety database for performing analysis)

Background relevant to evaluation: According to RSI, Parkinsonism is listed in warnings and precautions.

Source: Sponsor’s drug safety database, Medical literature, and Clinical data.

Interval case characterisation:

Post marketing data:

Number of cases reported: XX (X % of all cases)

Gender: Female (XX), Male (XX), Unknown (X)

Source: Spontaneous (XX), Post marketed study (X), Solicited (X), Literature (X), Clinical study (X)

Age: Range 18 to 82 years; Mean 61 years; n=X

Country: USA (XX), Japan (X), Israel (X)

Relevant PTs: Parkinsonism (XX), Bradykinesia (XX)

Event Seriousness: Serious (X), Non-serious (XX)

Event Outcome: Not recovered (X), Recovered (X), Unknown (14)

XX cases (XX adverse events) were reported during the interval period that includes: Parkinsonism (XX), Bradykinesia (XX)

There were two cases where the dose of <<medicinal product>> was decreased as a response to events and the events were recovering/recovered and hence a causal relationship cannot be ruled out.

Literature Data:

There was no significant information received from literature sources.

Clinical Trial Data:

There was no information received from clinical trial data.

Case Analysis: Each relevant and significant case needs to be analysed for proper causality assessment, followed by discussion and conclusion.

 16.4 Characterization of Risks

This subsection includes characterization of important identified and important potential risks based on cumulative data (i.e., not restricted to the reporting interval), and describe important missing information.

Depending on the nature of the data source, the characterization of risk can include, where applicable:

• Frequency
• Numbers of cases (numerator); precision of estimate, taking into account the source of the data
• Extent of use (denominator) (expressed in, e.g., numbers of patients, patient-time) and precision of estimate
• Estimate of relative risk, precision of estimate
• Estimate of absolute risk, 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., age, pregnancy/lactation, disease severity, hepatic/renal impairment, relevant comorbidity, 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
• 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, e.g., number of patients studied, cumulative exposure or long-term use) should be discussed.

For PBRERs of products with several indications, formulations, or routes of administration, where there might be significant differences in the identified and potential risks, it might 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
• Risks associated with non-prescription use (for substances that are available as both prescription and non-prescription products)

Example:

Now let us take the “sedation” as an example of a potential/identified risk-

Risk Characterization for Sedation:

Frequency:

Post-marketing sources

No. of cases: XXX (XX %)

Clinical trials

No. of cases: XX (X %)

Seriousness:

Non serious (XXX), Serious (XX)

Event outcomes

Recovered (XXX), Not recovered (XXX), Recovering (XX), Fatal (XX), Unknown (XXX).

Severity and nature of risk: Moderate to Severe.

Background incidence/prevalence: The background incidence of sedation among patients with <<approved indication>> is not known. Due to the nature of the disease, patients are often receiving other medications which may also cause sedation, and which may confound assessment.

Risk groups or risk factors: Higher than therapeutic doses. Concomitant use of alcohol or other sedating drugs which may have additive effects

Potential mechanisms: Sedation is considered to be an extension of the primary pharmacological activity of the <<medicinal product for which PBRER is being written>> as it is associated with depletion of dopamine.

Preventability: Sedation is primarily dose-related and disappears when doses are reduced to XX or XX mg/day. Close monitoring during titration can help manage this side effect.

Potential public health impact of safety concern: Sedation will impair a patient’s ability to function normally; including impairing ability to drive or operate complex machinery. Sedation associated with <<medicinal product>> use is likely to impact quality of life parameters.

Evidence source: Drug Safety Database, Reference Safety Information, and Literature.

16.5 Effectiveness of Risk Minimization

This subsection summarizes relevant information that has become available during the reporting interval concerning the effectiveness and/or limitations of specific risk minimization activities for important identified risks. Insights into the effectiveness of risk minimization activities in any country or region that might have utility in other countries or regions are of particular interest. Information can be summarized by region, if applicable and relevant. When reporting in a PBRER the results of evaluations that are relevant to only one region and that have become available during the reporting interval, the results should be provided in regional appendices.

Example:

For a safety concern, sponsor might propose either routine or additional risk minimization activities (sometimes both). Below are some examples for risk minimization activities.

After having analyzed the data, we conclude that the current risk management activities and routine risk minimization is appropriate for this product and there was no increased frequency and severity of the listed safety concerns observed during the reporting interval. Besides the routine risk minimization measures there are no additional risk minimization measures required for this medicinal product.

“Sometimes, this section would not applicable for a medicinal product, for which there are no identified risks and proposed neither routine or additional risk minimization activities.”

17. Benefit Evaluation

17.1 Important Baseline Efficacy/Effectiveness Information

This subsection summarizes the information on the efficacy/effectiveness of the medicinal product as of the beginning of the reporting interval, and should provide the basis for the benefit evaluation. This information should relate to the approved indication(s) of the medicinal product listed in the reference product information (see section II.D (2.4) of this guidance). For medicinal products with multiple indications, populations, and/or routes of administration, the benefit should be characterized separately by these factors, where relevant. The level of detail provided in this section should be sufficient to support the characterization of benefit in PBRER section 17.3 and the benefit-risk assessment in section 18.

 Example:

<<company medicinal product>> is indicated in some countries for relief of symptoms of <<approved indication>>. <<company medicinal product>> has been shown to be effective in providing relief of these disorders.

The latest evidence-based guidelines from the <<Literature evidence>> recommend that clinicians prescribe <<company medicinal product>> as first line treatment of <<intended indication>>, provided that the risks of <<list of some common expected adverse reactions>> are managed appropriately.

A brief description is necessary on each disease (approved indication(s)), epidemiology, summarization of efficacy/effectiveness information found from literature abstracts/articles.

 17.2 Newly Identified Information on Efficacy/Effectiveness

This subsection includes the new information on efficacy/effectiveness in approved indications that may have become available during the reporting interval.

For approved indications, new information on efficacy/effectiveness under conditions of actual use should also be described in this section, if available.

“New information about efficacy/effectiveness in uses other than the approved indication(s) should not be included”, unless relevant for the benefit-risk evaluation in the approved indication. Information on indications approved during the reporting interval should also be included in this section.

New information on efficacy/effectiveness might also include changes in the therapeutic environment that could have an impact on efficacy/effectiveness over time (e.g., vaccines, emergence of resistance to anti-infective agents).

The “new benefit” information would be summarised which is identified either from post marketing studies or from literature articles/abstracts.

If there was no new benefit information on approved indications, below statement might be sufficient to include for this subsection.

“No significant newly identified information related to efficacy and effectiveness of company medicinal products was identified during the reporting interval.”

17.3 Characterization of Benefits

This subsection provides an integration of the baseline benefit information and any relevant new benefit information that has become available during the reporting interval for approved indications. This section should provide a concise but critical evaluation of the strengths and limitations of the evidence on efficacy/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
• Generalizability of treatment response across the indicated patient population (e.g., information that demonstrates lack of treatment effect in a subpopulation)
• Adequacy of characterization of dose-response
• Duration of effect
• Comparative efficacy
• A determination of the extent to which efficacy findings from clinical trials are generalizable to patient populations treated in medical practice

The level of detail provided in PBRER section 17.3 should be sufficient to support the analysis of benefit-risk in section 18. When there are no new relevant benefit data, section 17.3 should provide a characterization of the information in section 17.1 of the PBRER. 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 section should be succinct.

Description of approved indication related studies and significant findings, summarizing the comparative efficacy information with other medicinal products of same authorized indication etc., This subsection could be not applicable, If no new information identified during the reporting interval.

18. Integrated Benefit-Risk Analysis for Approved Indications

This section provides an integration and critical analysis of the key information presented in the sections 16.4 and 17.3.

This section provides the benefit-risk analysis and should not simply duplicate the benefit and risk characterization presented in sections 16.4 and 17.3.

1. Benefit-Risk Context: (Medical Need and Important Alternatives)

This subsection provides the brief description on medical need for the medicinal product in the approved indications, and summarized alternatives (medical, surgical, or other, including no treatment) for the same intended indication.

Example:

The medical need: a brief description of disease (approved indication) epidemiology, requirement for medical therapy for addressing/treatment/alleviation of symptoms from the <<approved indication>>

Important alternative treatments: List of current alternative medicines, procedures present in the market for the <<same approved indication>>.which might include other drugs of similar therapeutic use, or surgical procedures etc.,

2. Benefit-Risk Analysis Evaluation: (A benefit-risk profile is specific to an indication and population).

For medicinal products which are approved for more than one indication, benefit-risk profiles should be evaluated and presented for each indication individually. If there are important differences in the benefit-risk profiles among populations within an indication, benefit-risk evaluation should be presented by population, if possible.

The 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 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 sections should be carried forward for integration in the benefit-risk evaluation.
• The context of use of the medicinal product should be considered: the condition to be treated, prevented, or diagnosed; its severity and seriousness; and the population to be treated.
• With respect to a key benefit(s), the following factors should be considered:

its nature, clinical importance, duration, and generalizability, as well as evidence of efficacy in non-responders to other therapies and alternative treatments. The effect size should also be considered. If there are individual elements of benefit, all of them should be considered (e.g., for therapies for arthritis, reduction of symptoms and inhibition of radiographic progression of joint damage).

• With respect to key risk(s), the following factors should be considered:

its clinical importance should be considered (e.g., nature of toxicity; seriousness; frequency; predictability; preventability; reversibility; impact on patients; and whether it arose from off-label use, a new use, or misuse).

• The strengths, weaknesses, and uncertainties of the evidence should be considered when formulating the benefit-risk evaluation. A description of how the uncertainties in the benefits and risks have an impact on the evaluation should be provided. Limitations of the assessment should be discussed.

A clear explanation of the methodology and reasoning used to develop the benefit-risk evaluation should be provided:

• The assumptions, considerations, and judgment 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 included in the benefit-risk evaluation. When there is important new information or an ad hoc PBRER has been requested, a detailed benefit-risk analysis should be provided. 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.

Example:

The benefits of <<medicinal product>> consist of <<detailed description of approved indication(s)>>.

These benefits have a major clinical importance as they are directly associated with a reduction in end organ damage and comorbid conditions such as coronary disease or stroke, both associated with high mortality and disability.

Duration of the benefits is directly related to regular medication intake.

<<medicinal product>> benefits are generalizable as they are derived from methodologically sound double blind and open label studies involving large number of subjects.

Individual elements of benefits are <<therapeutic benefits after treatment with <<medicinal product>> for <<approved indications>>

There were two important identified risks, eight important potential risks and one element of missing information categorized at the beginning and during the reporting period.

Strengths, weaknesses, and uncertainties of the evidence are:

Strengths

• Evidence of benefits was yielded in numerous methodologically sound clinical trials involving large number of subjects of both sexes with <<approved indications>>.
• Efficacy comparable to that of other drugs commonly used for <<approved indications>>.
• The benefits yielded in clinical trials generalizable to population seen in everyday clinical Practice.
• Long presence of <<company medicinal product>> in many markets and consequently, familiarity of prescribers with << company medicinal product>>.
• Consistent recommendations for << company medicinal product>> use across different currently valid treatment guidelines in <<intended/approved indications>>.

Weaknesses:

• Lack of more recent study data to further qualify and quantify the risks associated with << company medicinal product>>.
• Data in non-responders to other treatments are lacking, although this is mitigated by the current treatment recommendations.

Uncertainties:

Although most risks can be considered predictable and/or preventable with patient-tailored dosing, the currently available data are mainly from post-marketing sources and therefore limit a full assessment of the actual risk involved. Similarly, under reporting from post marketing sources is well known. Thus, the cumulative reporting frequency may possibly represent an underestimation of actual occurrence.

Impact on the benefit/risk evaluation:

The risks of << company medicinal product>> concern potentially serious conditions, which might have a major impact on the health of the individual patient. The limitation of the benefits assessment is a lack of more recent study data to further qualify and quantify the risks associated with << company medicinal product>>, which is common with products available for a long time and as generics.

No action is required with regard to the closed signals. All the closed signals will be monitored through routine pharmacovigilance activities.

Based on the available safety and efficacy data for << company medicinal product>>, the overall benefit-risk profile of << company medicinal product>> remains favourable.

19. Conclusions and Actions

This section provides a conclusion about the implications of any new information that has arisen during the reporting interval, in terms of the overall benefit-risk evaluation, for each approved indication, as well as for relevant subgroups, if appropriate. Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the MAH should assess the importance of further changes to the reference product information and propose changes, as appropriate.

In addition, and as applicable, the conclusion should include preliminary proposal(s) to optimize or further evaluate the benefit-risk balance, for further discussion with the relevant regulatory authorities. This might include proposals for additional risk minimization activities. These proposals should also be considered for incorporation into the risk management plan (e.g., the E2E pharmacovigilance plan and/or risk minimization plan, as appropriate). If required by applicable regional laws and regulations, the MAH should provide, in a regional appendix, information on any final, ongoing, or proposed changes to the national or local authorized product information.

Example:

There were no new or changing relevant safety findings identified during this reporting period. The cumulative and PBRER review period safety issues for << company medicinal product>> were reviewed and there were no changes in the frequency and/or severity of the safety issues.

The safety data remain in accord with the previous cumulative experience and the safety information presented in the << company medicinal product>> RSI document.

The benefit/risk assessment was considered to remain favourable (and unchanged) and supports routine pharmacovigilance and risk minimization activities (labelling).

20. Appendices

The PBRER should be accompanied by the following appendices, as appropriate, numbered as follows:

1. Reference Safety Information (Current RSI during the preparation of PBRER)
2. Cumulative Summary Tabulation of Serious Adverse Events from Clinical Trials and Interval/Cumulative Summary Tabulations from Marketed Experience
3. Tabular Summary of Safety Signals (if not included in the body of the report)
4. Listing of Interventional and Non-Interventional Studies with a Primary Objective of Post-Authorization Safety Monitoring
5. List of the Sources of Information Used to Prepare the PBRER (when desired by the MAH)

The PBRER can also be accompanied by regional appendices, as appropriate, to fulfill the national and regional requirements.