What skills are important in PV other than PV?

 What skills are important in PV other than PV?

Many of us who are SME (Subject matter experts) are always under impression than knowing my domain and being hardworking will help me in my career and i don't need anything else. I was under the same rock, being a nerd my whole life (off course i am doctor) i was huge believer of this myth at least for a year or two in my new job.

Fortunately, i had great mentors, bosses, colleagues and leaders who bust my myth and helped me build whatever career i wanted to achieve one step, one skill and one learning and one training at a time.

 So if you are in pharmacovigilance career and you are limiting your learnings to regulatory guidance documents, clinical and pharmacology knowledge then you are in a surprise because guess what is needed for all that knowledge you have to be put into actions and then demonstrate you bring value and outcome to the organization- yes you guessed it those are your non-technical skills which people call soft skills, behavioral skills etc.

It never too late for us to shift from what my favorite author says "knower to learner". SO lets dive in what other skills you need apart from sound and working PV knowledge.

 1. Project management: 

Yes, if you don't have PMP certificate its ok, but working knowledge is must. Because PBRER, DSUR, PSUR, Signal reports, RMP, PSMF -they are projects. 

They have multiple writers, compilers, reviewers and they have strict external timelines. So dust your skills on what it means to have RACI matrix, KPI, KOM. Even a SUSAR is project with 15day/7 day timelines and you have data entry, medical review or quality review from different people that needs to happen on time with quality and final step is submission. 

How do you handle this projects? will you be their manager ? nope, not always and even if you are then you have more responsibility . This are individual tasks given to you if you have team or not. So you need to learn how to clear accountable, responsible delegation, expectation setting and tracking to deliver this.

2. Communication skills:

 How to have clear, defined and courageous and brave communications. This means written and verbal. You are responsible for safety of patients, your voice matter. Own your expertise and communicate the impact of product in signal meetings, in PSUR, DSUR or even ICSR (DOES THIS CASE impacts case, is it related or not related). Communicating clearly so you present your knowledge is must. 

You work in strictly regulated environment and strict timelines, asking for what you need and giving what you promised needs clear communication with who, when, what and how and also why.

3. Time management:

Time management skills, which I like to say is time utilization is to use your time effectively to deliver expected results. These means allocate your time properly and accomplish tasks efficiently. 

When you have SUSAR, a section in PSUR and signal report due in one week, how do you allocate time? If you are a manager add to this list, performance reviews, unexpected sick leaves and so on. Learning how to allocate time is must.

 4. Prioritization: 

You can achieve more when you start dedicating time to the right things. But how do you know what those things are? Eisenhower's principle explains this nicely, which you can google. What it means is in PV everything can feel like its urgent, so use your SME skills, know what are timelines for SUSAR, PSUR, DSUR etc so you know which to prioritise. In addition, some tasks may simply don’t have defined timelines, then also you need to know how to prioritise them.

 5. Business skills: 

As PV SME, you may work for CRO/Vendor or MAH. When you are working in service side, you will be required to know how to do business capability presentations, upsell, crossell, pricing for ICSR, SUSAR, PADER etc. You will be required to negogiate, engage and finalise business agreements with partners, clients etc. Even if you are working for MAH/Pharma you need to know what is strategy for my product, what is the revenue, what are the plans and how PV can support that product to ensure its thriving in market.

 6. Tools: 

Many people believe that as PV SME they just need to know safety database, literature database and maybe few signal database and that’s the only tools they need to know. Yes we will spend majority of our time in the PV systems, but we will need to use word (author, compile, review) PSUR ,DSUR, RMPs so you need to know how to use word ( insert footnotes, bibliography, TOCs, hyperlinks and more complex commands). You need to know excel- how to calculate number of case, events, present cases by patient age, gender in pivot table, create signal reports etc. We also need to know power point, leading, contributing to kick of meetings for aggregate reports, RMP, PSMF, Signals etc.

This are very few that i have listed, and yet i am still developing them. The goal is to keep learning and implementing.

Written by:

Dr.Shraddha Bhange.

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Signal Detection: Basics

Signal Detection Basics

Signal detection is the most extensive and critical topic in PV. While it is almost impossible to cover it in one simple blog, we can try to introduce it at least.

 Definition of Signal: New potentially causal association, or a new aspect of a known association between a medicinal product and an event or set of related events which may require some action for ensuring patient safety. A signal may only be relevant for a particular medicinal product or a whole class of medicinal products.

 

1. Sources of Signal detection:

 

1. ICSRs 

2. Clinical trial data , Spontaneous data, Scientific literature

3. Experimental and/or non-clinical findings which has a significant impact on human exposure

4. Databases with larger datasets when the signal was detected from national or marketing authorization holder-specific databases (Eudravigilance)

5. Healthcare databases that may provide information on characteristics of exposed patients and medicines utilization patterns (VigiBase-WHO, FAERS)

6. Information from other regulatory authorities worldwide

2. Steps in Signal detection:

2. 1.  Detection: 

Using signal sources , first step is to detect signal by using any of the below     methods as per the disease, product portfolio and RA requirements.

2. 2.Validation:

 Once a signal is identified, validating it with different methodologies, and  assessing   if a true causal link is present between the event and drug.

2. 3.  Analysis and prioritization: 

Once we validate that a signal is indeed present, the next step is to analyze if the identified signal (event) is serious, severe, reversible, irreversible and its impact on public. A event that causes a irreversible damage or requires a very risky and expensive treatment obviously needs high prioritization. Based on this there is definition of signal, High, medium and low priority signals.

2.4. Assessment and recommendation for action: 

Once we prioritize a signal, we need to ensure there is action taken to minimize the impact of the signal. E.g. if a signal is identified as drug induced liver injury, then we may have to inform HCPs via USPI/training to monitor the liver enzymes of patients

3. Signal detection methods:

3.1.    Quantitative: High volumes e.g. EVDAS, Vigibase then Computational and statistical, Data mining algorithms, Disprotionality and eRMR

3.2.    Qualitative: Low volumes e.g. Company safety database then ICSR from safety database, Aggregate safety data, Literature and AESI

3.3.    Semi-quantitative: Both together then Qualitative for safety database with low volumes and Statistical methods for high volumes from HA database

 

        4.Examples of actions to be taken:

 

4. 1.    Urgent Dear Health Care Professionals Communication warning of potentially increased risk of adrenal crisis during the swap over the period, with the risk theoretically being highest in youngest patients, and those with least adrenal reserve or other comorbidities.

4. 2.    An update to the reference safety information.

4. 3.    An update to the EU RMP

 

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Dr.Shraddha Bhange.

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ICH guidelines- Summary of E2F 
DSUR

Any PV professional aiming to work in or already working in PV has to be aware on how to navigate and use the ICH  guidance documents. The PV professional who has to write, review or compile a DSUR is supposed to know the DSUR guidance from ICH on finger tips.

• MAH (marketing authorization holder) are asked to prepare DSUR for a fixed period of time for each drug or active substance by health authorities for investigational products.

• A single DSUR from each investigational drug which should suffice to give complete information on evolving safety profile of drug . This will also help regulators to have only one report to review,  consistency in companies will be achieved and will also decrease number of reports generated.
• DSUR will mainly be focused on clinical trials of investigational drug (vaccines and biologics inclusive). The DSUR should also include other finding that can be beneficial in adding about safety profile or benefits of drug.
• DSUR should also include about comparators whenever needed in safety profile discussion about the investigational drug in case of comparison studies.
• A single DSUR can be submitted by MAH for all indications, dosage and intended population for that investigational drug.
• MAH are supposed to submit DSUR as annual report starting from the developmental international birth date which is the date when the MAH got first authorization to conduct trial in any country.
• MAH are required to submit DSUR to regulatory authorities and in addition if requested by ethics committee or institutional review boards.
• The document used for labeling i.e reference safety information is investigators brochure(IB), which if not available can be replaced by local product label.
• DSUR should also emphasize on any other trials data if available other than their own MAH sponsored trials, non clinical data, data from literature, spontaneous reports.

• DSUR should also have data on lack of efficacy, region specific AE or ADR.
• DSUR should conclude with overall safety, any changes in reference safety information, any change in safety action plan etc.
• The information in DSUR should also cover ongoing risks and any resolved risks.

The content of DSUR is off Course available on ICH guidelines.

To sum the content are introduction of drug, its worldwide marketing status, actions taken in that period of time of report to cover any safety issues, any changes in reference safety information i.e IB, clinical trial that was undertaken details regarding it if ongoing and completed trial, how many patients/subjects were exposed as in cumulative exposure, line listings and summary tabulations of all ADR (adverse drug reaction ) and SAE(Serious adverse event), any other significant findings from clinical trials and non interventional  studies.

The information in DSUR can form basis of safety specifications and risk management (ICH E2E) that we discussed last blog.

Reference: https://database.ich.org/sites/default/files/E2F_Guideline.pdf

  

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Dr.Shraddha Bhange.

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ICH guidelines- Summary of E2D

 ICH guidelines E2D 

POST-APPROVAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

Any PV professional aiming to work in or already working in ICSR has to be aware on how to navigate and use the ICH E2D guidance.

ICH E2D goes into details about the various scenario's a MAH has to navigate while processing, analyzing and submitting ICSR from post marketing scenario. 

Below are generic timelines, format and content outlined from the guidance document with my interpretations.

Reference:https://database.ich.org/sites/default/files/E2D_Guideline.pdf

1. ICSR content and format: 

• Cases of adverse drug reactions that are both serious and unexpected are subject to expedited reporting. The reporting of serious expected reactions in an expedited manner varies among countries. 
• Non-serious adverse reactions, whether expected or not, would normally not be subject to expedited reporting.
• The definition of life threatening and medically significant should be revised which clearly specifies the criterion for this seriousness criteria.
• Source of case i.e. spontaneous vs solicited are well explained

• CIOMS is accepted format for submission. 

2. Literature

• The frequency of the literature searches should be according to local requirements or at least every two weeks.
• If the product source, brand, or trade name is not specified, the MAH should assume that it was its product, although the report should indicate that the specific brand was not identified. 
• If multiple products are mentioned in the article, a report should be submitted only by the applicant whose product is suspected. The suspect product is that identified as such by the article's author. 

3. Digital media

• MAHs should regularly screen websites under their management or responsibility for potential ADR case reports. 
• MAHs are not expected to screen external websites for ADR information. 
• However, if an MAH becomes aware of an adverse reaction on a website that it does not manage, the MAH should review the case and determine whether it should be reported. 

4. Other pointers

• Medical review should be done for clinical completeness of case, is diagnosis provided, what are diagnostic procedures, what other possible factors could cause this, what more information's is needed?
• Follow up attempt should be made for serious cases . For incomplete cases as well follow up to ensure 4 minimum criteria are seek should be documented. The priority and expectation for follow up is mentioned.

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ICH guidelines- Summary of E2E

ICH guidelines- Summary of E2E

                                                   Pharmacovigilance Planning 

Any PV professional aiming to work in or already working in PV has to be aware on how to navigate and use the ICH  guidance documents.

• ICH E2E goes into details about a Safety Specification and Pharmacovigilance Plan that might be submitted at the time of license application.  
• This module describes two aspects i.e.  Safety Specification and Pharmacovigilance Plan.
• Pharmacovigilance plan can also be developed for products already on the market (e.g., new indication or major new safety concern).
• The same plan can correlate to the Common Technical Document (CTD), especially the Overview of Safety [2.5.5], Benefits and Risks Conclusions [2.5.6], and the Summary of Clinical Safety [2.7.4] sections, includes information relating to the safety of the product. 

1. Safety specification:

This can be started to build during pre clinical phase and allows regulators and the industry to be aware of safety profile of product and supporting data and this can be utilized to build the PV methods to address same in future. 

1.1. Non clinical : The data on toxicity, pharmacology and drug interactions

1.2 Clinical : World wide experience i.e. patient exposure, regulatory actions, new or different safety issues

1.3 Populations not studied in pre approval phase: Special category i.e. children, elderly and pregnant females etc.

1.4 AE/ADR

1.5 Epidemiology of disease

1.6 pharmacological class effects

1.7 Summary- Summarize the important identified, potential risks and missing information.

2. Pharmacovigilance plan:

This plan very closely resembles the risk management plan sections. Below are template sections.

2. 1. Summary of Ongoing Safety Issues 

2.2 Routine Pharmacovigilance Practices

2.3 Action Plan for Safety Issues

2.4 Summary of Actions to be Completed, Including Milestones

3. Pharmacovigilance methods:

The guidance documents also describe various methods and which one can MAH chose and what principles to use for same.  For e.g. for spontaneous reports data mining techniques can be used but what are pro and cons for same. Stimulated reporting, case series , active surveillance, registries can be used as well for PV and the definitions, advantages and details are well explained. 

Reference:https://database.ich.org/sites/default/files/E2E_Guideline.pdf

  

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Dr.Shraddha Bhange.

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ICH guidelines- Summary of E2C

ICH guidelines 

E2C PERIODIC BENEFIT-RISK EVALUATION REPORT (PBRER)

 

Any PV professional aiming to work in or already working in for aggregate reports like PSUR/PBRER has to be aware on how to navigate and use the ICH E2C guidance.

ICH E2C goes into details about the various scenario's a MAH has to navigate while preparing the PBRER. It also breaks down each section in PBRER and how to write it and what are expectation in each section.

Below are generic timelines, format and content outlined from the guidance document with my interpretations.

1. What ?

•    The main purpose of PBRER is as name suggests talk about risk and benefits a medicinal product has and how they justify in terms of patient safety and treatability.
•    PBRER should cover on efficacy/effectiveness of medicinal product that becomes available during the period it covers as said in ICH guideline.
•      The new risk/benefits are to be compared with previous information of risk/benefits the medicinal product had.

2. How?

2.1 Single vs multiple PBRER?

•  Single PBRER for an active substance is sufficient. This meaning if an active substance in various indications, dosage and regimens have same data lock points (DLP) is it sufficient to have one PBRER. 
• However in a different indication or different route altogether permission from local HA needs to be taken on how PBRER will work in this situation.

2.2 Labelling document :

 

• The labelling document used for basis about adverse medicinal product reactions being listed or unlisted should be clearly specified .
• The common documents used is company core data sheet for (CCDS) in that section of company core safety information(CCSI) section, USPI (US package insert) European summary of product characteristics (SmPC), this are all reference safety information (RSI) documents.
• During PBRER submission if any new safety signal was identified then it should be clearly included and mentioned that this was a new change made in reference safety information of labeling documents.
• The change made in RSI maybe addition of any new safety signal, events in listedness, potential risk, overdose, contraindication, removal of any indication etc.

3. When are they needed? Timelines:

• PBRER are required by health authorities (HA) and regulatory authorities (RA) on periodic basis.
• The periodicity depends on local and regional timelines. 
• PBRER should offer information about new risks or new safety information about the medicinal product that emerged in the period time it covers, PBRER are mostly covering period of 1 year/6month/2 years from the last PBRER that was submitted to HA.
• The periodicity of PBRER is decided from international birth date of medicinal product (date of the first marketing approval for any product containing the active substance corresponding to PBRER you are making).
• The period start date is from last PBRER or as finalized per HA requirement till the Data lock point (DLP) which is a date designated as cut off data date to be included in PBRER).
• The time given by Health authorities to MAH is – for PBRER covering intervals of 6-12 months-within 70 calendar days of DLP.
• For PBRER covering intervals in excess of 12 months within 90 calendar days.
• For PBRER requested on adhoc basis by HA 90 days or as specified in ad hoc request.

4. PBRER Format:

The PBRER format is given in ICH guidelines starting from title, table of contents etc.

The PBRER format is designed in such a way that it covers following important points:

1) Introduction to the active substance/medicinal product under PBRER, Its worldwide marketing authorization status.

2) Actions taken by MAH in reporting interval about any safety concerns in that period of PBRER.

3) Any changes made by MAH during PBRER time interval in safety information of labelling documents or in any sections of medicinal product.

4) Patients exposed- In clinical trials (if any ongoing), spontaneous reports from patients exposed by marketing of medicinal product in market collected via hospitals, pharmacy etc.

5) List of serious unexpected, serious expected, non serious unexpected and non serious expected.

6) Summary of all safety information in completed clinical trials, ongoing clinical trial, post marketing sources from ICSR (individual case safety reports) or literature, patient programs etc., long term follow ups. All sources of adverse medicinal product reactions to be included herein.

7) A brief overview of safety which should include new identified risk, potential risk, increased incidence of known risk, lack of efficacy, overdose, new indication should be mentioned, any missing information on new signal should be also explained.

8) A brief overview of benefits- Evaluation of known benefits and new information on same should be explained.

9) PBRER should also be having any action planned, new study planned, medicinal product registry data collection planned etc. in it.

Reference:https://database.ich.org/sites/default/files/E2C_R2_Guideline.pdf 

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Dr.Shraddha Bhange.

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ICH guidelines- Summary of E2B

ICH guidelines- E2B Data elements for  Transmission of Individual Case Safety Reports (ICSRs)

 

As we talked about some pointers from ICH guidelines in my last post  E2A, in this post i will try my best to take out summary of E2B guidelines. Summarizing E2B guidelines is very difficult because it has multiple layers scattered over multiple documents. 

This document describes the requirements of reporting ICSR in clinical trials. 

Reference here https://admin.ich.org/sites/default/files/inline-files/E2B_R2_Guideline.pdf

CLINICAL SAFETY DATA MANAGEMENT : DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS E2B(R2)

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

1.  Minimal information

• one identifiable patient - any one of several data elements is considered sufficient to define an identifiable patient (e.g. initials, age, sex); 
• one identifiable reporter - any one of several data elements is considered sufficient to define an identifiable reporter (e.g. initials, address, qualifications); 
• one adverse event/reaction (or outcome); 
• one suspect or interacting drug.  
• Sender’s (case) Safety Report Unique Identifier 
•  Type of Report
•  Date of Most Recent Information for This Report
•  Dose This Case Fulfil the Local Criteria for an Expedited Report? 
•  Worldwide Unique Case Identification 
•  Reporter’s Country Code 
•  Sender’s Organisation 
•  When type of report=‘Report from study’, Study Type Where Reaction(s) / Event(s)Were Observed

This applies to all types of ICSRs including initial case reports, follow-up information, and cases to be amended or nullified. 

All the information available should be reported in fully structured format using the relevant E2B(R3) data elements and applicable standard terminologies. 

Those terminologies include; ISO (country codes, gender codes and language codes), MedDRA (e.g. medical history, indication, and reaction / event), UCUM (units of measurement), and ISO IDMP (see Section 3.2.1.1 for details).

2. Some pointers:

• ‘Future dates’ cannot be transmitted in an ICH ICSR message.
• Metric units should be used exclusively. 
•  For ICSR reporting, MedDRA is commonly used in the ICH regions.
• Defintion and details on when to use null flavours, unknown and blanks
• ICH recommends that when a poorly documented case is reported, then the clinical judgement should be exercised
• For the cases being reported from health authorities where the qualification of reporter is not found, then primary reporter is health authority and qualification of reporter to be entered as unknown.
• ICH database does not accept values such as < and > in its format. They recommend using standard website for providing standard units and values, like lab values units to be referred from http://unitsofmeasure.org/track

While i have tried my best to explain things, original guidelines should or has to be refereed, my understanding may not replace or be substitute to them at all.

Written by:

Dr.Shraddha Bhange.

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