Audits and Inspections in Pharmacovigilance

 Audits and Inspections in Pharmacovigilance

 Audits or Inspections word can catch anyone off guard, but at the same time its a huge learning opportunity for us to find deficiencies/gaps in process and how we handle our routine operations.

 
Being part of audit and inspections in the past, but also recognizing that I am not yet expert on this or far from expertise, I just figured learning by sharing would be a good revision to be audit/inspection ready.

 What are some basic readiness actions we can take from operations team (meaning the team that is actually handling pharmacovigilance on daily basis) and excluding the Quality Assurance (QA) team who is actually the owner/leader on audits/inspections. 

There is depth of information on type of audits, inspections, how to prepare for them , corrective action, inspection report etc, but I will focus only on actual easy and simple topics that are expected from any PV operations team member. Obviously, QA team and higher leadership roles in PV will have to know more than described herein. 

To give an example and put things in perspective, MHRA (Medicines & Healthcare products Regulatory Agency)  conducted 22 inspections in 1 year between April 2017 and March 2018, which took tremendous amount of time, money and resources of both, pharma companies and MHRA. During these inspections, MHRA identified 89 major findings in risk management plans, noncompliance in quality systems, analysis of safety data, and management of adverse drug reactions.

1) Document readiness :

All the document pertaining to processing of adverse drug reaction reports like receipt of the reports by fax, mail, hard copies or soft copies received via website, call center, sites, consumers/patients etc should be appropriately archived as per internal SOP (in line with HA requirements) and be available to be reproduced if requested by auditor or inspector.

 

If there is involvement of other vendor such as CRO (contract research organization)  or any other company to whom part of or all of PV is outsourced then both MAH (marketing authorization holder/pharma company)  a SDEA and additional document as needed on data archival should be clearly mentioned. Adverse drug reaction reports (SAE forms/ email form patient) etc are the most critical document as they contain personal information of patient protected udner various country specific laws and regulations, hence there storage and archival should be very clearly defined and followed.

 

All the other documents e.g. not limited to investigators brochure, CCDS, protocol, SmPC, labelling documents, DSUR,PBRER, clinical study reports etc should also be defined regarding there availability (common share file location -access restricted) and who is responsible for ensuring most recent versions are available to the team for reference and the update process should be defined. 

 

The SOP should clear enough to address who, what , how and when at company level so the process are robust. More details on this can be found  on GVP Module I.  All the team members processing the adverse events and handling PV should have training compliance and training matrix to showcase the SOP are followed.

 

2) Process consistency:

Process should be standardized to ensure all team members have clear defined role and responsibilities to handle data. e.g. The adverse drug reports received from reporter, consumer, investigators etc may not be completely consistent or documented, there has to be audit/inspection readiness document to prove that there are document to help in identifying and making this reports more coherent for PV practices. Hence how to to do follow up for missing information for adverse events, and what type of questions are critical for should be part of process.

3) PV professionals: 

There has to be clear documentation on handling of PV functions per requirements by local and National HA eligibility rules. The CV , JD (Job description), training records, training matrix should be clearly documented and regularly updates per requirement. Whenever required, only read and understood document may not be enough, but quiz or exam to ensure understanding should be implemented.

Many health authorities need medically qualified persons to handle PV functions of casualty assessment and medical narrative of adverse drug reaction reports. This has to be documented and also the training and required qualification to be updated.

 

4) PV practices:

There has to be clear documentation on each and every process. For e.g. mail communication with reporters, investigators patients, consumers to reproduce CRO/MAH attempt to have complete medical documentation of all adverse drug reactions (ADR) reports. All calls, e-mails etc between any PV professional at CRO or  MAH also documented to make sure each ADR/PV follow up attempts are tracked correctly.

 

The PV practices should also have assessment check points, if the process is effective and is being followed or not. Regular assessment of each SOP and process described in it should be planned and carried out. 

 

5) PV function readiness:

 Any request or actions from health or regulatory authorities in form of requests, questions, query, audit finding should be actioned and discussed across all PV team . Any action or root cause that is found to be due to other department should be communicated as such to them. Pharmacovigilance department should always be audit/Inspection ready, as it is department that concerns safety of patient and any finding or gap will impact all other departments and patients safety.

 

6) PV Database:

Knowledge on technical details on database used by MAH/CRO should be across PV team, and any data privacy measures, threats etc discussed and documented properly to ensure there are measures to avoid patient data leak etc. Appropraite team such as IT, Database vendors have to be involved to address this.

Thanks,

 Dr.shraddha

 

 

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 References: 

 

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

2.                https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency

3.                https://www.pharmacovigilanceanalytics.com/opinion/pharmacovigilance-audits-inspections-and-pv-analytics/

4.                http://www.hpra.ie/homepage/medicines/regulatory-information/pharmacovigilance-and-post-authorisation-safety/pharmacovigilance-inspections

5.                https://www.gmp-compliance.org/gmp-news/pharmacovigilance-inspection-metrics

 

 

 

 

 

Writing Company assessment in pharmacovigilance

 

With changing times, it is said that we have lost a lot of our attention span and this if applied to our reading, makes us to read something quickly and come to conclusion. 

This is exactly what physicians, health authorities, responsible HCP (Healthcare Professionals) want to read when they read adverse event report preferably CIOMS/MedWatch. They just want to get idea regarding the reported adverse event and the suspect drug and what does the company's position is on this.

Medical assessment is known as company comment, sponsor comment, MAH comment and so on  but in this blog we will term it as medical assessment. The medical assessment or sponsor assessment or company comment is exactly the place where you will find this information.

What is medical assessment?

This is short description (generally not more than 4 to 5 sentences) regarding Sponsor's position with respect to the reported Adverse Event (AE) and Sponsor's suspected products and its relationship to AE in a very brief and conclusive way.

Who should write it?

Many Sponsors* and Regulatory authorities* prefer safety physician’s i.e certified medical doctors to  write it especially for Clinical Trials (CT) and Serious cases. However non serious and post marketing adverse event reports can be handled by experienced pharmacovigilance individuals who are not medical doctors per se but are HCP’s with proper training and expertise. In fact, regulatory guidelines are also not stringent regarding requirement of only medical doctors to write medical comment for all cases in PV , and same is being followed widely in industry.

Prerequisites for writing a comprehensive company comment:

     1.    Know the safety profile of drug- Refer to IB,RMP,SmPC,PIL .This helps to understand the mechanism of action and safety profile of suspect product in relation to the reported event.

 2.     Causality assessment- It is a topic, that will be explored in detail in another blog. However the important prerequisite is that causality assessment has to be done so you know your position as to is it a related or not to suspect product. This helps in writing sponsor assessment so that you know how and what to write. 

3.       Know the clinical presentation of the event, it is important to know the disease pathophysiology, risk factors etc so as to explain the event and correlation to drug.

4.     Know the time to onset/Latency (temporal relationship of the event and product).

5.      Knowing safety profile of other concomitant medications. This is not always very easy, especially in patients when conmeds are reported as none or many. The trick is first go by class of drugs and then download the SmPC/PIL/USPI of relevant drugs from company website/RA websites. (You can find such relevant websites on my previous blog)

What and how should it be framed?

Medical assessment is free text field in any Safety database used by Sponsor. Most Sponsors have a standard template to help drafting it.

Some common do’s are:

1.  Use full generic drug names (i.e. for the active ingredients) only; no abbreviations.

2.   If the case is not assessable due to poor documentation, describe what additional information is needed to determine causality. Ensure you send follow up for this missing information.

3.  If required, provide reference of case definitions/literature to support the assessment.

4.  Provide the statement regarding the current safety profile of drug in relation to current RSI and event (listedness).

Some common don’ts are:

1.   Be concise (e.g. do not repeat case demographics which are already mentioned in case narrative i.e age & sex, unless they contribute to the medical assessment).

2.    Avoid abbreviations including obvious one’s as well  e.g COPD,DM,URTI,HB etc .

3.   Do not include calendar dates but the number of days from exposure to event (e.g. 2 Days after treatment started) i.e latency; it is acceptable to give approximate dates (e.g. after about two months or 2 years when more appropriate).

4.    Avoid mentioning unsubstantiated or non-scientific sources to frame sentences.

5.    Avoid using very definitive and specific terms or personal opinions like it is highly impossible, not at all related etc.

6.    Avoid mentioning assessment for other company suspect products when not needed or when data is inconclusive.

Take home message : 

It is important to remember that the medical assessment should make medical and scientific sense and is standardized ( conveying  same meaning to every reader). It is company statement and the writer should remember that it can be challenged during audits/inspections.

*Sponsor/Marketing Authorization Holder/Manufacturer and RA/HA/NRA/CA (Regulatory Authorities/Health Authorities/National Regulatory Authority/Competent Authority) are used interchangeably for ease in blog but have different definition.

 Written by:

Dr.shraddha Bhange.

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Risk Management Plan (RMP)

 The most complicated and tedious document as per me in my PV career is RMP (Risk Management Plan). 

Who requests and why?

An RMP is requested for any medicinal product undergoing a authorisation application by various health agencies e.g. EMA, Japan etc.It is also an requirement to maintain one for medicinal product for its lifecycle.

What is RMP and how it helps?

An RMP serves as a planning document for assessing how the risks identified for a medicinal product would be managed.The RMP serves as document that can discuss about conducting PASS, additional pharmacovigilance activities required for certain risks that need monitoring. An MAH (Marketing Authorisation Holder) should start with dRMP (Developmental Risk Management Plan) once the clinical trials are initiated. Aggregate reports such a DSUR  serves as bridge/link for dRMP . The aggregate analysis done during each review period for DSUR will parallely help in identifying risks during the development of product.

The dRMP then can be drafted to become RMP.  RMP also serve as guidance for drafting SMPC/USPI/PI sections pertaining to safety.

Frequency or timelines of RMP?

RMP is a live document that has no DLP or no specific timelines for update once finalised/submitted. It should be updated on need basis, meaning whenever there is update with respect to any risks or risk minimisation measures identified while writing a aggregate reports, signal detection analysis, ICSR, Literature monitoring etc.

Template:

I have copied the RMP template below from EMA website (reference links below). Most of the health authorities do not have any standard template for RMP. Many MAH follow EU-RMP or REMS (FDA) template and is accepted.

Part I Product(s) overview 

Part II Safety specification 

Module SI Epidemiology of the indication(s) and target population(s) Module SII Non-clinical part of the safety specification 

Module SIII Clinical trial exposure 

Module SIV Populations not studied in clinical trials 

Module SV Post-authorisation experience 

Module SVI Additional EU requirements for the safety specification 

Module SVII Identified and potential risks  

Module SVIII Summary of the safety concerns 

Part III Pharmacovigilance plan (including post-authorisation safety studies)

Part IV Plans for post-authorisation efficacy studies 

Part V Risk minimisation measures (including evaluation of the effectiveness of  risk minimisation activities) 

Part VI Summary of the risk management plan 

Part VII Annexes 

Discussion about template:
The product specification would particularly be aligned with the product details which we can furnish form IB/CCDS/USPI . The part that is particularly tricky is where we need to mention identified ,potential risks and missing information (all definitions in GVP module V). Also it depends on which stage product is in, for a product that is yet to be approved, potential risks and missing information would be more. All other modules are self explanatory, the important one I can highlight is module SVII identified and potential risks which should explain each risk individually, the clinical details of it, diagnosis, treatment available, its severity and effect on population and how MAH will put forth the measures to minimize or prevent it.

It is important that MAH should monitor the outcome of each risk minimization measures that were included and implemented for risks.  If the outcomes or assessment of measures present need of change or additional measures for risks, the RMP should be updated and the measures should be immediately acted upon.

References:

https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/pharmacovigilance/risk-management/risk-management-plans

Written by:

Dr.shraddha Bhange.

Connect with me Via comments below or on linkedin. (I do not respond to Facebook messages)

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