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.

Written by:

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.

Written by:

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.

Written by:

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

Written by:

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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Basics of ICSR (Case processing)-Revision

 

Basics of ICSR (Case processing)-Revision

No matter where you are in your Pharmacovigilance career, almost always your interview will start with ICSR processing questions ( till you specialize or diversify or reach senior leadership position). Although below are key basics but when you are in stressful situations of showcasing your knowledge to either a interviewer or a potential client on your understanding of ICSR it is challenging to address this questions and hence a quick skim of some tricky situations and questions helps.

1. 4 minimum criteria

  Tricky scenarios to look out for:

1. An article retrieved with your brand name product which does not specify any patient details but just "number of patients" - is it valid or invalid case and moreover how do you handle this situation.

2.  A case downloaded by an SDEA partner on behalf of MAH in another territory and forwarded 15 days late, is serious unlisted in their territory and you are responsible for only US territory- is it expedited case or not?

This are very grey area scenario which will be based on where the MAH has marketing authorization i.e. which regulations are applicable, FDA, GVP etc. And based on this regulations how the internal SOP and process are framed.

So in First scenario- you should first download full text if not already done, try to download the reference data from its original source to get patient details, if not do follow up. As conservative approach you could create a case for safety analysis at the time of signal detection. 

2. Decoding the regulations:

Regulatory guidance documents need to be referred on ongoing basis, this are not read once and done kind of study documents. So let go of notion or expectation that you will know all the guidance requirements on tip of your fingers. Each situation is different, but knowing where and which regulations to read is expected from professionals the least.

3. Source of ICSR

Yes we know there are two source of ICSR, Solicited and Unsolicited or Spontaneous. But there are variations which you need to be aware. An non company sponsored trials cannot be solicited unless there is agreement between MAH and third party for data sharing in that case- it will be either unsolicited or solicited but in category of "Other trials". This will depend on safety database you are using what options it has at the backend. Also Partner case, Health authority cases, Compassionate use etc. are also different categories in source of ICSR.

4. Data entry:

This includes seriousness, labelling, expectedness, coding of events and products (MedDRA &WHO-DD), Reportability and narrative.

4. a. Seriousness:  Knowing seriousness criteria and using it in real world are two different things. When do we use medically significant? It is not when no other criteria is fulfilled, but in fact when if event left untreated could have led to any of the other 5 criteria. IME or DME list is applicable only when MAH is in that territory or there is explicit mention in the process at SOP level to use this. However in absence of such documented process and clarity, its good to go with conservative approach of upgrading to serious when present in IME list.

4.b. Labelling : Knowing the correct document to use for labelling is the first step, its easier in most situations as there is only one IB, USPI or SmPC. 

• It is tricky when you have multiple versions of IB or different labelling documents in various territories. In this tricky situations rely on using the correct one based on date of occurrence, CCDS or any documented process for same. 
• It is also important to use the correct sections, e.g. in IB its section 6.5 Reference safety information or section for investigators to assess listedness.
• For the USPI – Use whole label to assess events Include Warnings and Precautions, Adverse Reactions ,Clinical Trials Experience, Post marketing Experience, Use in Specific Populations, Patient Counseling Information, Patient Leaflet  
• Overdose section only applies to events reported with overdose.

•        Generally, if an outcome (e.g., death) reported for adverse event exceeds the usual outcome for that adverse event as described in the labeling document, the associated event should be considered unlabeled.

•        Non-specific terms where the meaning of the adverse event can vary (e.g., feeling abnormal, drug intolerance) should be considered unlabeled, unless these terms are present in the labeling document. Additional information should be sought to obtain clarification.

 

4.c Causality : 

• In spontaneous cases it is implied causality meaning "related" by default however most MAH will leave it blank in event screen in database for both company and reporter unless explicitly stated. The causality can be described with evidence in company comments.
• In clinical trials, its binary causality meaning related and not related. For FDA, Sponsor causality drives reportability and for EMA the highest causality drives reportability. 

4.d Coding with medDRA and WHO-DD:

• MedDRA stands for : Medical Dictionary for Regulatory Activities. 
• It is used for coding events, patient history, indications, investigations, product issues, medication errors etc. Soft coding need to be avoided i.e. coding to lesser serious or severe term. 
• Abbreviations cannot be subsumed.
• Diagnosis cannot be subsumed based on signs and symptoms are reported.
• Specificity needs to be maintained
• Severity needs to be correctly captured i.e if high blood sugar is reported, Diabetes should not be coded.
• WHO-DD: A drug dictionary proves useful when tabulating medication usage because it classifies the same medication, often known by different names, into a single name. Its used to code suspect, cosuspect, conmeds, treatment medications etc.

4.e. Narrative writing

• Narratives are expected to be submitted for all cases reported expeditiously to any regulatory authority but are useful and should be made available when needed for other types of reports and purposes
• EU requires narrative for all cases, except non serious but MAH may choose to have narrative for all cases in their database
• Knowing what is most relevant for drug event pair and limiting narratives to that, e.g. history that is closer to event in duration or clinically to be included, conmeds that are most relevant to the drug and event. Lab tests that are repeated multiple times add no value but in that case records first and last day lab tests or those that are clinically relevant only.

5. Special case scenario

    Special Situations are non-standard medical conditions that provide valuable information (e.g. clinical and safety) about a medicinal product, even when they don’t occur in association with an adverse event or medical condition; therefore, should be recorded/ reported/ monitored.

•   Examples include abuse, misuse, medication errors, overdoes, off label use, product issues etc.​
• Knowing when to capture just special situations without AE is important, most MAH will database this case and then do follow up and some may use other database or category to track this.
• This data is required to be summarized in aggregate reports and signal detection 
• It provides insights in new indication, quality issue, product usage that impact quality or safety.

6. Medical review

Medical review is performed by trained safety physicians and is mandate for clinical trials cases.

• Writing company comment- refer to my blog on this topic for notes
• IND annual safety reporting for US FDA- will cover this topic in another blog. This is summary of index case (Serious unlisted and related by company/sponsor) and other similar cases in safety database. The FDA requires this analysis report for all SUSAR cases within 7 or 15 days to FDA, Investigators and ethics committee to provide most recent and evolving safety profile of investigational product.

7. Regulatory submissions:

Every regulatory authorities have their own timelines and its important to know the applicable timelines for the product you are handling and which RA is applicable. In general below are timelines that can be shared that are applicable commonly .

• Expedited safety reports with death or life threatening as seriousness criteria= As soon as possible but within 7 days of AE receipt date should be notified to all required stakeholders.
•  Expedited Safety Reports with other seriousness criteria = As soon as possible but within 15 days of AE receipt date should be notified to all required stakeholders.
•  CIOMS/MedWatch for manual submission to stakeholders.
• •Electronic reporting to HA database- XML/Manual via eudravigilance portal

 

Written by:

Dr.shraddha Bhange.

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What, how and who of PV for Freshers

 What, how and who of PV for Freshers

There are lot of freshers who approach industry experts to find them job in PV.  While its a good idea to begin with, but turning this idea into reality takes little bit more effort. So instead of just doing the traditional route of sending CV and message on Linkedin or whatsapp, add below steps to your plan as well.

Step 1 : What is it that you are applying for? What is PV?

Yes, we all can find definition of pharmacovigilance on number of websites, youtube video and that is a great start. But dig deeper. Read, understand and digest the definition in true sense . This will allow you to stand out because instead of traditional method of blurting the textbook definition you will be able to "REPRODUCE" definition as you understand not as its written in textbook.

So what is PV? 

"Pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem."

1. It is collection of adverse event/side effects/ drug problems from patients, consumers and Healthcare professionals.

2. It is collection, monitoring and analysis of adverse events and their continuous monitoring to ensure the medicinal products in market are safe and effective for patients.

Step 2 How PV helps in patient safety?

The reported Adverse event data is analyzed to ensure the risks that are associated with the product/drug are manageable, treatable, reversible or preventable.

The adverse events collected are then translated into meaningful information for patients and consumers to make informed decisions regarding product safety and usage.

The information is also utilized to communicate to HCP (Doctors, Nurses etc) so they are aware of adverse events and how to  prescribe the product, educate patients on risks, prevent the risks or manage the risks. 

Step 3 Who reports the adverse events and where

1. All HCP can report adverse event (including pharmacist, nurse, lab technicians, doctors, students).
2. All patients and consumer can report too.
3. There is no legal obligation or action for reporting, neither there is any fee to be paid or earned.
4. Adverse events are reported to pharma companies toll free number, email id etc
5. Adverse events can also be reported to countries national regulatory authorities e.g. in India it is CDSCO, US it is FDA etc.
6. Reporting adverse event is free of cost, all reporting forms are available free on internet 

Step 4 Why you want to join PV?

Tricky question, try to answer it as genuine as possible but dont give too much philosophical answers as well.

1. The growth opportunities are great considering PV is mandatory through all stages of drug development to marketing.

2. The career is secure in terms of having mandatory regulations to pharma companies to have PV dept.

3. The ideology of helping patients by working and ensuring the medicinal product safety provides job satisfaction.

Thanks,

Shraddha