Summary of Module VII – Periodic safety update report

 Summary of Module VII – Periodic safety update report

Continuing the series on Guideline on good pharmacovigilance practices, in this blog i will jump right into module VI having covered module I , II, III, IV, V and VI in previous blogs.

This module describes the PSUR requirements.

Overall, the module does go in more and clear details on expectations and its best to read module thoroughly and completely when one has to write, compile, review or submit PSUR.

Reference:https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vii-periodic-safety-update-report_en.pdf

What is PSUR?

It is legally required document for a medicinal product that needs to be submitted by MAH to agency and/or national competent authority after the drug is approved at a set frequency within defined timelines.

The format and content of PSUR is provided in this module and also refers to PBRER format as per the ICH-E2C(R2) guideline. 

This is scientific document which compiles the safety data related to the particular medicinal product. Analysis of this safety data in terms of its impact on benefit-risk profile of product. 

Why is it written?

 To determine whether there are new risks or whether risks have changed or whether there are changes to the risk-benefit balance of medicinal products

When is it written?

Usually PSUR is required for new authorized products or products that are launched recently in new indication or formulation etc. Products for whom safety profile is not yet established. With this background, the PSUR is usually not required for generic or OTC products unless requested by agency or NCA.

The timelines are below as per module.

• within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12 months (including intervals of exactly 12 months); 
•  within 90 calendar days of the data lock point (day 0) for PSURs covering intervals in excess of 12 months; 
•  the timeline for the submission of ad hoc PSURs requested by competent authorities will normally be specified in the request, otherwise the ad hoc PSURs should be submitted within 90 calendar days of the data lock point.

How is it written?

The sections along with short expectation for each section is summarized from detailed requirements for each section in module.

Part I: Title page including signature

It should be clear who are the signatories at organizational level. Generally it is head of PV, CMO, Safety physician, medical writer.

 Part II: Executive Summary 

This section should provide summary of product in terms of indication, review period, analysis of data and its impact on benefit-risk assessment, exposure data. The section is used for wider audience (non-PV) so the aim is to keep it concise and clear. 

Part III: Table of Contents (TOC)

As the PSUR is very lengthy documents easy navigation via TOC is mandatory.

Section 1 Introduction

This covers products introduction, review period, patient exposure, disease/indication.

Section 2 Worldwide marketing authorisation status

This is generally presented in tabular format which explains the products status across worlf, IBD, approval country and date.

Section 3 Actions taken in the reporting interval for safety reasons

This includes actions for the product in investigational (clinical trial ) or marketing. The actions alongside reasons should be provided. E.g. Change in RSI (SmPC, USPI), Protocol modifications, suspension, withdrawal, pack size, restriction on use, communication to consumers or HCPs.

Section 4 Changes to reference safety information

Any changes to RSI implemented during the review period i.e. change in warnings, precautions, contraindications etc should be explained.

Section 5 Estimated exposure and use patterns

In this section we use sales data to calculate patient exposure and other data such as from clinical trials. The age group, gender, different usage etc. can also be found from this data for categorization.

Section 6 Data in summary tabulations

This refers to data from safety database. No need to present single ICSR cases, but cumulative assessment. If there are few cases that needs to be described then the narrative should not be copy paste from CIOMS, but clinical assessment of narrative.

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

Present the data analysis form each study in terms of new safety information herein. Tabular format of ongoing or completed studies by study ID, indication, age/sex etc can be presented.

Section 8 Findings from non-interventional studies

Aggregate analysis of data and its impact from various non interventional studies such as observational studies, epidemiological studies, registries, and active surveillance programs.

Section 9 Information from other clinical trials and sources

This section should provide pooled aggregate analysis of data from other clinical trials and data on medication errors etc.

Section 10 Non-clinical data

This section will provide analysis and summary of major safety findings from non-clinical in vivo and in vitro studies (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the reporting interval.

Section 11 Literature

This section will describe the articles that were found to be relevent form the risk-benefit analysis of product.

Section 12 Other periodic reports

If there are other periodic reports developed then summarize finding from that report herein. 

Section 13 Lack of effect

13. This section should summarize data regarding lack of efficacy, or lack of efficacy especially to product's used treat or prevent serious or life-threatening illnesses.

 Section 14 Late breaking information

 This is not per se cases received unless they are index case and promoted as signal. This refers to clinically significant new publications, important follow-up data, clinically relevant toxicological findings and any action that the marketing authorization holder, a data monitoring committee, or a competent authority (worldwide) has taken for safety reasons.

Section 15 Overview of signals: new, ongoing, or closed

This section refers to overview of all signal in review period. The signal can be provided as tabulation as well. New signal and their status. Ongoing signal and if any change in its status or relevance. Closed signals and there outcome is presented.

Section 16 Signal and risk evaluation

This should not be repetition of section 15 but rather interpretation of the data on signals. An clinical analysis of signal and how they relate to current risks. An mapping can be provided for the signals to current risks and how they are presented in current RSI or what are risk minimization measures for this risks.  

Section 17 Benefit evaluation

This provides baseline efficacy data and effectiveness of product in the approved indication or new indication if the data is found such. 

Section 18 Integrated benefit-risk analysis for authorized indications

Summary of benefit risk assessment of the product and conclusion on any planned actions for maintaining the same. How the current benefits and risks are addressed for the product and the data suggests the change or it remains same.

Section 19  Conclusion

• Summary of the data
• Changes or no changes to benefits
• Changes or no changes to risk
• Integration of risk and benefits
• Proposed plan on how to balance the BR  e.g. any risk minimization measures

Section 20 Appendices of PSUR

1. RSI

2. ICSR tabulations from safety database

3. Tabular summary of safety signals

4. List of all clinical trials

5. Regional appendices

It is important to note which reference safety is used during PSUR, there are multiple variations given in the module. It is most common to use the RSI that was effective at the end of the review period.

Written by:

Dr.Shraddha Bhange.

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Written by:

Dr.Shraddha Bhange.

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Support the cause of better rural education with me:ThinkSharp Foundation http://thinksharpfoundation.org/#home

Summary of Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products

 Summary of Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products

Continuing the series on Guideline on good pharmacovigilance practices, in this blog i will jump right into module VI having covered module I , II, III, IV and V in previous blogs.

This module describes the ICSR requirements.

Overall, the module does go in more and clear details on expectations and its best to read module thoroughly and completely when one has to collect, process, analyze and submit ICSRs.

1. Definitions in ICSR : When we are processing cases, we are confused on requirements, going back to basics and looking at definitions helps. Definitions are provided for Adverse drug reaction, seriousness criteria special case scenario e.g. misuse, abuse, medication error, lack of efficacy etc.

2. Processing of ICSR : The requirements of ICSR processing, including identifying correct source type i.e. solicited, unsolicited. Type of cases and its requirements spontaneous, literature and clinical trials.

3. Submission of ICSR: Submission format, content and timelines are provided.

"The submission of serious valid ICSRs is required as soon as possible, but in no case later than 15 calendar days after initial receipt of the information by the national or regional pharmacovigilance centre of a competent authority or by any personnel of the marketing authorization holder, including medical representatives and contractors. This applies to initial and follow-up information." ICSR can be submitted electronically and follows ICH guidelines.

4. Nullification of ICSR: This is when the case is created erroneously then a follow up will eb submitted notifying EMA and then nullified.

5. Amendment of ICSR: When a previously submitted ICSR has to be corrected (without getting follow up) then amended ICSR should be submitted. The amended fields should impact the meaning of case i.e. seriousness, listedness, company comment, causality etc.

Reference:https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-and-submission-reports-suspected-adverse-reactions-medicinal-products-rev-2_en.pdf

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Dr.Shraddha Bhange.

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Summary of Module V – Risk management systems

 Module V – Risk management systems 

Continuing the series on Guideline on good pharmacovigilance practices, in this blog i will jump right into module V having covered module I , II, III and IV  in previous blogs.

This module describes the risk management plan (RMP) requirements, structure and content.

Overall, the module does go in more and clear details on expectations and its best to read module thoroughly and completely when one has to write, compile, contribute or review RMP.

1. What is RMP?

“The aim of a risk management plan (RMP) is to document the risk management system considered necessary to identify, characterize and minimize a medicinal product’s important risks.”

RMP describes the risk associated with the product, the severity, seriousness, outcome and impact of risk on patient and general population. It also should describe the disease (Indication) and the product details.

2. When is it written?

RMP is written at the time of approval of product, renewal of product and in the time period when the first PSUR following the first 5 year renewal is due for submission. RMP is a living document meaning it needs to be updated as the information's regarding product gets updated. RMP is also updated at the time of PSUR 

3. How is it written?

GVP module describes the template and sections thoroughly . Providing the gist of sections below.

Module I Product Overview- Description related to product

Module II Safety specification- This section refers to identified risk, potential risk and missing information, it also describes the epidemiology, clinical and non clinicals data, patient exposure and risk. The risks need to be described in terms of their severity, seriousness, outcome, treatability and impact on patient and general population.

Module III Pharmacovigilance plan (including post-authorization safety studies): This describes the risk and there status (identified risk if it was potential before), severity, frequency and impact on patients. It describes routine and additional pharmacovigilance activities.

 Module IV Plans for post-authorization efficacy studies:

Module V :Risk minimization measures (including evaluation of the effectiveness of risk minimization activities): This section defines the routine and additional risk minimization measures. E.G. Legal status of products, Smpc, pack size etc

Part VI Summary of the risk management plan:

This section is must and is also published on the EMA website, the audience is broad and hence this section should be well written and explained. It should describe the product and its status, indication, its current risk status (identified, potential and missing information) and the risk minimisation measures currently implemented for same.

4. Why is it written?

Ideally RMP is legal and compliance requirement, but the reasons for writings an RMP is to ensure all the risks are summarized alongside the detailed, clear and concise plan on how to minimize them. This ensures patient safety. Also the risk minimization measures and the plan to monitor those effectiveness then becomes legally binding furthering the cause of patient safety.

In nutshell, a RMP is very detailed scientific document that requires lot of expertise in PV, clinical and medical side of it. This should hence be prioritized to be written with experts that have all this background and also the timelines and effort to complete the document should be strategized very well in advance.

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Dr.Shraddha Bhange.

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Summary of GVP IV Pharmacovigilance audits

 

Summary of GVP IV Pharmacovigilance audits

Continuing the series on Guideline on good pharmacovigilance practices, in this blog i will jump right into module IV having covered module I , II and III  in previous blogs.

This module describes the pharmacovigilance audits why are they conducted, what is the goal, who conducts and when are they conducted.

Overall, the module does go in more and clear details on expectations and its best to read module thoroughly and completely when one has to lead, participate or contribute to an audit themselves. 

An audit is an opportunity for they system owners and individuals to identify how cna we prevent any issue/concerns that could possibly impact the process and may lead to impact on product or patients. It is an opportunity to identify if the systems, tools, process and personnel are effective and as per regulations and industry standard. 

Here is the link https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-iv-pharmacovigilance-audits-rev-1_en.pdf

What is audit?

"An audit is a systematic, disciplined, independent and documented process for obtaining evidence and evaluating the evidence objectively to determine the extent to which the audit criteria are fulfilled, contributing to the improvement of risk management, control and governance processes".

An audit determines the deficiency in the pharmacovigilance system and its supporting tools so that corrective and preventive actions (CAPA) can be implemented.

 When is it conducted?

Audits are conducted based on internal strategy by MAH or agency or NCA. There can be planned audits and for cause audits. The frequency of audit can be determined based on PV systems and requirements. MAH are required to conduct regular audits and also enter major and critical findings along with the CAPA in the PSMF

Who conducts it?

Trained and exert Auditors can only conduct audits. They need to have required skills and trainings. Pharmacovigilance knowledge, skills and abilities as well as Quality standards, knowledge, skills in audit principles, procedures and techniques; and RA applicable laws, regulations as well as processes and systems background; management system and organizational system. 

How?

An audit that should be conducted required planned agenda, strategy, objective, sufficient written documentation of each of this and appropriate time to be given to all the stakeholders involved. Audit will involve looking at SOP, Process, interview the personnel, training records etc. An official audit report with written documented findings i.e. critical, major and minor will be released to the owner of PV system.

The owner of the system and process i.e. department heads will then have to populate written responses to each findings with CAPA and timelines.

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Dr.shraddha Bhange.

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Summary of GVP III Pharmacovigilance inspections

 (GVP) Module III – Pharmacovigilance inspections

Continuing the series on Guideline on good pharmacovigilance practices, in this blog i will jump right into module III having covered module I and II  in previous blog.

This module describes the pharmacovigilance inspections, why are they conducted, what is the goal, who conducts and when are they conducted.

Overall, the module does go in more and clear details on expectations and its best to read module thoroughly and completely when one has to lead, participate or contribute to an inspection themselves. 

Here is the link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-iii-pharmacovigilance-inspections_en.pdf

1. What is inspection ?

An inspection is done by national competent authority (NCA) or EMA agency of MAHs systems, processes and personnel to ensure they are fulfilling all legal obligations required to ensure risk benefit monitoring of product authorized in EU for safeguarding patient safety. 

2. When are inspections conducted?

1. Routine inspections : This are conducted routinely as per agency's risk monitoring based approach.

2. For cause inspections : This inspections are conducted when agency or NCA is inspecting any non compliance or failure of MAH to fulfill any PV obligations.

"As a general approach, a marketing authorization holder should be inspected on the basis of risk-based considerations, but at least once every 4 years"

Interesting examples given in module are below:

2. 1. Risk benefit balance

When MAH fails to inform about withdrawal or suspension of product

Any change in risk benefit was not communicated properly 

2.2. PV obligations

 Not submitting ICSR, PSUR or any other documents with quality and on time

2.3. Failure to respond to NCA/Agency requests

Not responding with adequate data and/or correct data at correct time

3. Who conducts inspections?

Inspector appointed and approved by agency and/or NCA.

4. Types of inspections: 

4. 1. Routine inspections : Conducted routinely as part of risk based approach at agencies end.

4. 2. For cause inspections as noted above some of the causes.

4. 3. Pre authorization inspections : This inspections are conducted for MAH who are applying for first time authorization in EU and Agency/NCA wants to ensure MAH has robust, efficient PV process

4. 4 Post authorization inspections: This inspections are conducted as follow up to preauthorisation once the approval is granted to ensure the MAH is legally compliant and also has all the required process and systems in place

4.5 Announced and unannounced inspection- as the name suggests some inspection are preplanned and informed with agenda and details to MAH i.e. announced and some are unannounced when the agency/NCA has reasons to conduct the same

Other types are follow up, remote, system specific, product specific inspections.

5. Common process or systems that are inspected

1. ICSR- Death and SUSAR cases are picked up

2. Products- those that have been recently approved or have been identified with new signals/risks or safety concerns

3. Aggregate reports - PSUR for products that was delayed, inadequate or has inconsistent data 

4. Signal or risk management : Signal process overall especially documentation of any downgraded or closed/invalid signals and for risks that have been recently identified and for which there are minimization measures in place

5. Products or clinical studies that are closed and have been used as basis for approval . Any study for which GCP inspection flagged an issue.

Ideally, the more detailed module should be referenced to know more about inspection planning, reasons, outcomes and expectations. 

6. Outcome of inspections:

A MAH will be required to provide and responds with documented evidence to agency/NCA for every inspection observation, minor or major findings with stipulated timelines for every corrective or preventive actions. An agency or NCA may take action on MAH based on this which maybe - warning, withdrawal, suspension, conditional approval etc.

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Dr.shraddha Bhange.

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Summary of GVP II (Guideline on good pharmacovigilance practices ) modules- GVP II

(GVP) Module II – Pharmacovigilance system master file (PSMF)

Continuing the series on Guideline on good pharmacovigilance practices, in this blog i will jump right into module II having covered module I in previous blog.

This module describes the requirement, content, legal obligations and process for PSMF. 

1. Background 

• All MAHs are obligated to provide PSMF for all the medicinal product that are approved or under approval process in EU. 
• The document is summary of pharmacovigilance system, which is assessed by each countries regulatory agency or as it is called in EU "national competent authorities"  during marketing authorisation application(s) or post-authorisation. 
• PSMF may not be required for traditional homeopathic and herbal medicines but description of PV process is must and EMA/RA may request PSMF too.
• MAH can delegate the PSMF creation, maintenance and registration but it has to be explicitly stated and however the responsibility lies with MAH

2. Registration and maintenance of PSMF

• At the time of marketing authorisation application, the MAH to submit PSMF electronically 
• Once electronic submission is done, MAH gets the PSMF reference number, which is the unique code assigned by the EudraVigilance (EV) system to the master file when the EudraVigilance Medicinal Product Report Message (XEVPRM) is processed.
•  Once the product is approved, the PSMF number will be linked to the same product in  EVMPD product code(s). 
• All PSMFs must be registered in the Article 57 database
• PSMF physical location should be in EU or closest in EU where all PV activities are done. If the PV activities are sub contracted and/or conducted outside EU then PSMF location is QPPV location. The electronic PSMF should also be located at direct shared file for QPPV and relevant stakeholders.
• Any change  in PSMF should be immediately updated and informed to QPPV. 
• Changes that are must to be notified to QPPV are described in GVP, refer for details.

3. What is content of PSMF?

• The PSMF should describe the pharmacovigilance system. 
• The content of the PSMF should discuss and showcase how the MAH will utilize and ensure the global availability of safety information for medicinal products authorized in the EU to ensure patient safety. 
• PSMF should provide summary of PV process and systems and wherever possible the documents supporting this will undergo process change hence to be added as annexures
• PSMF should also provide QPPV details, Organizational position of QPPV, medicinal products covered
• PSMF should also provide details about computerized systems, infrastructure and tools
• PSMF should also provide details regarding how MAH will collect AE data from which sources, how this will be utilized to monitor risk-benefit analysis, details about PSUR, signal detection and risk management, how safety concerns will be communicated 
• PSMF should also provide details about delegation of any of this activities and details for same

4. When is PSMF due?

      1. As mentioned above, PSMF is required at the time of approval. 

     2. Any change in location of PSMF or QPPV or major changes should be done within 30 business' days so it reflects on EV portal.

5. How and who ?

• A PSMF is a very lengthy document and generally there is no single writer or owner when creating it. But there should be one compiler and a records is maintained by MAH on each section as to who will populate the section, who is owner and what are timelines. 
• This RACI (responsible, accountable, confirmed and informed) matrix is must especially when PSMF is owned by multiple stakeholders (MAH, QPPV, Vendors etc) . 
• This file along with PSMF should be accessible to all stakeholders involved. 
• There should be clear description and agreement for all stakeholders on their responsibilities and timelines.

 

Overall, the module does go in more and clear details on expectations and its best to read module thoroughly and completely when one has to compile, write or contribute to PSMF themselves. 

Here is the link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-ii-pharmacovigilance-system-master-file-rev-2_en.pdf

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Dr.shraddha Bhange.

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Summary of GVP (Guideline on good pharmacovigilance practices ) modules- GVP I

 

(GVP) Module I – Pharmacovigilance systems and their quality systems

Anyone who starts working in PV or is working in PV has to know the GVP modules sooner than later. Although this documents are freely available on internet, we have to refer them on ongoing basis as per our questions rather than just reading it once. Also, despite reading them, they do appear overwhelming as its daunting to extrapolate what exactly is requirement. Hence my attempt to summarize it below.

This module describes the quality management systems that should be part of pharmacovigilance process. The details provided act like guiding principles of establishing pharmacovigilance processes in terms of SOP, Infrastructure, Technology, People and Organizational level expectations. It also provides insights into what are measures that are expected to showcase if the PV process is working efficiently.

Summarizing a high level points from the module for revision below.

In a nutshell, the expectations are below

Ø  Having a PV process that lay down in written agreements that PV process are robust, effective and legally complaint i.e. SOP, Work instructions, user manuals, trainings materials and records

Ø  Having system in place that can communicate and ultimately prevent or treat identified adverse reaction in patients and general population via different channels to HCP/Patients etc

Ø  Having process to disseminate most correct and current product related safety information to consumers and patients

Ø  Having process in place to collect AE, analyze and take actions via signal, risk etc. to ultimately prevent, correct or treat AEs

The module also provides insights on how MAH can ensure the process is effective by establishing measurable outcomes wherever possible to check if the QMS is working.

Usually below are some standard outcomes that are used as KPI (Key performance indicators): (Extrapolated from guidelines)

•      Serious and non serious cases submitted on time
•       PBRER, DSUR or any other aggregate report format submitted on time
•       Any signals detected and there submission on time
•      Any new risk or change in risk that was identified and how was it communicated to HCPs, Patients and consumers 
•      Any recent audit finding and how they were handled - measures taken and the timelines meet
•      Any non compliance in process- how they are tracked and corrective and preventive actions implemented

An audits are scheduled on set frequency internally and or risk based audits can also be conducted.

Other important details described in the module are below

1. Quality cycle and its steps 

2. Organizational level requirement for each process to have objective clearly defined in terms of roles, responsibilities, timelines, frequency etc

3. Involvement of leadership in each aspect of process to ensure PV process is efficient to meet legal obligations

4. Objectives of PV system to ultimately fulfill obligations for patient safety

5. Requirements for technology's and infrastructure and how to integrate quality.

6. Having compliance and record management system

7. Having system to track any non compliances i.e. audit, inspection, CAPA etc

For detailed read on the link below: 

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-i-pharmacovigilance-systems-and-their-quality-systems_en.pdf

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Dr.shraddha Bhange.

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