Disclaimer

The ideas, views and opinions expressed in here in blog or comments and profile represent my own views and not those of any of my current or previous employer .They are based and taken from regulatory guidance available freely and my interpretations from my experience.

Friday 26 July 2019

Follow up of adverse events


Introduction to Follow up:

As humans, one of the many things that we enjoy is solving puzzles and mystery. And so true, because they give us satisfaction of putting things in place, where you say "Aha, so this was like that, good that now i know the answer to puzzle". Likewise, if somebody is telling you a story and the person suddenly stops, we pressurize, beg and even threaten them to complete the story.
This is what a follow up in PV is! Not the threatening and pressurizing part (off course :)) but bit of begging maybe (just joking).




What is follow up?

Adverse events reported to us by reporter are often incomplete, they always send us information as per their understanding of AE. We, PV professionals,need more information to put the story or puzzle together. That's a follow up, where we send our questions needed to understand AE better, to reporter of AE, so that new information will help us to solve the mystery or to complete the story.




Why to do Follow up?
Industry perspective: Follow up activity in PV is a very critical aspect because it allows to collect complete medical information regarding the reported adverse event.
Additional information  received via follow up, helps to perform single case causality and case level risk benefit assessment. Also, when you are doing aggregate safety report or signal detection activities, ICSRs having complete information are very helpful to complete case series causality, to do quantitative signal detection and risk benefit assessments.


Regulatory authority (RA):They have the same ideology as MAH, i.e. to collect the required data regarding adverse event to assess the case from a complete sense and to do signal detection and risk benefit assessments. Additionally, they look at process set up for follow up activities at MAH as indicator of robust PV system. 

Recommendations for follow up:
One aspect is mandatory type of questionnaire or follow up, which is done when one of four criteria for validation of AE report is missing. If a reporter reports an AE where 4 minimum criteria are missing (i.e. an event, a product, reporter identification or patient identification details) a follow up is immediately sent. This is a follow up for validity check and regulations clearly states that MAH must do it, before we categories any case as invalid. Minimum of 3 attempts are recommended to be made and attempts have to be documented.

Another follow up, is more about completeness of the AE from medical sense of the case/ ICSR. This follow up is to understand the occurrence of AE in context of patients’ pre-existing risk factors, be it medical history, conmeds, other non-clinical but significant abnormalities patient had and other such factors. This follow up can be done effectively by PV professionals who have good medicine understanding and PV experience.

Type of questionnaire:


Off course the type of questions that we need to ask reporter depends on individual patient, reported adverse event  term, type of report (serious,non serious,spon/CT). But, I am going to just give generic and basic overview below.


1. In a Clinical Trial (CT) case, we have a mandate to collect all the information needed to assess the reported AE. Follow up is easy and most the times, we get answers, as CT cases are monitored by PI (Principal Investigators) with their dedicated staff , hence they expertise and resource, in addition to obligation signed with MAH to provide required information.

CT cases are also important because safety profile of drug is not yet established, every case is looked as a potential signal .We use case definitions to define such case.

E.G. If we have a AE in CT of “Liver injury” we will collect patients risk factors such as history of liver disorder, alcoholism,Intake of herbal products, past liver enzyme levels and if not done, lab tests for hepatitis infection, liver enzymes etc. This is exhaustive follow up is needed and possible for CT Cases.

2. In Post marketing, follow up is not always easy, HCP and Patients are not keen on getting hassled or bothered with a big list of questions from MAH. Many times, they do not provide us their contact details or refuse to give contact details. In that case we have to be an expert in making questions easier for them and use specific questions only.

3. In serious post marketing cases, preference for follow up is given to unexpected and then expected AE’s. If patient has reported his/her HCP, its better to  contact them to provide details. 

Follow up questions are based on if the reported event is identified risk, potential risk, an AESI etc. In any case, we should make it easy for reporter to answer our follow up questions.

E.G. SAE of neutropenia is reported, we need to ask just enough question, not too many such as last 12 month neutrophil counts and not very less such as neutrophil count of that AE and no questions pertaining to exclude other causes of neutropenia.

4. For non serious cases, the key is to prioritize questions that will clear any possibility for upgrade of event to serious and event severity. And additional information that might add to quantitative or qualitative assessment of reported non serious AE in signal detection (increased frequency or severity) or add or change risk mitigation strategies of the reported event .

      For Non serious cases, it is also important to remember to ask about outcome and treatment, sometimes when we see patient received a treatment for non serious event that was administered in hospital, or treatment that is consistent with life threatening conditions, we realize the report is actually serious.


5. Type of questions and examples: Few generic questions for follow up are :
   
      Confirmation for diagnosis, reporting the diagnosis vis-a-vis symptoms and signs, providing supporting lab data to confirm diagnosis (e.g Xray details for AE reported as fracture, but not relevant for AE terms such as headache, fever, rash etc), risk factors especially when AE falls in Cardiovascular, Liver, Kidney and Immunology organ system, concomitant medications especially in old age patients, interaction type of AEs.



     Other follow up generic questions that are important to understand case and are common to any AE reports are start and stop date of event and suspect drug (to assess latency and temporal relationship), treatment received, clarification regarding typo errors, unclear or missing information.


      The trick is to assess the key factors for reported event that will help the case completeness .

For serious cases, minimum 3 attempts and for non serious 2 attempts are recommended before we consider and close case as “lost to follow up” but vaires as per MAH SOPs. Follow up is done via email, phone call or fax, ensure to document each follow up as per standard operating procedure.



References:
Few enslisted below:

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting
GVP Module VI – Collection, management and submission of reports of suspected
adverse reactions to medicinal products
FDA Postmarketing Safety Reporting Requirements for Drug and Biologic Products

Images-Shutterstock


Written by
Dr.shraddha Bhange.
Connect with me Via comments below. (I do not respond to Facebook messages)
Support the cause of better rural education with me:ThinkSharp Foundation http://thinksharpfoundation.org/#home

Saturday 13 July 2019

Pharmacovigilance- Knowledge Repository

What I like about working in Pharmacovigilance is the opportunity to learn new things everyday!

Keeping yourself updated with industry knowledge and upgrading your skills is important in every fields and also in pharmacovigilance. My opinion is, it is actually more important in pharmacovigilance, as this domain is tightly governed by laws, regulations and guidance’s set by regulatory agencies of country, which get updated or undergo changes frequently. Additionally there is an update in the medicine and scientific area of drugs too.

I thought of enlisting few websites or blogs that I found useful to keep myself updated on industry trends and updates in pharmacovigilance. This blog will not be covering websites or blogs or journals related to medicine as it deserves a separate write up.

https://www.cinglevue.com/growing-learning-mindset-whats/


1) Regulatory Agencies/Health Authority websites:
These websites are great source of information for enhancing knowledge or refreshing one's memory or simply keeping in touch with regulatory updates. If you subscribe to this websites, then any new updates from regulatory agencies will be delivered to you in your mailbox.
FDA for US regulations, EMA for European regulations, MHRA for UK regulations, TGA for Australia, PMDA for Japan,ANSM for France and so on.

1.1 FDA website- It is storage of vast knowledge on varied number of topics, but browsing the website is bit troublesome, but once you get hang of it, lot of required information and in fact free courses and documents become available to you. There is an option to subscribe (link below) to any new articles or changes that you can receive in email box:

https://www.fda.gov/industry/industry-notices-and-guidance-documents 

1.2 EMA website-It is very informative and user friendly website, navigation is quite easy and finding topics of your interest is bit easier. I have enlisted the main page of EMA, from here, navigation is possible to topic of your choice.


1.3 MHRA-This is a Website of UK’s Medicines and Healthcare products Regulatory Agency and is very informative. Especially availability of SmPC (Summary of Product Characteristics)/ package Insert/CCDS) in alphabetical order. Additionally, they do have lot of other information such as drug safety updates, recalls, rules and regulations updates etc.
 All the updates are easily visible on website.


1.4) CDSCO-The Central Drugs Standard Control Organization (CDSCO) website of India's regulatory agency is quite informative, but I feel the website needs more information and more updating on frequent basis. Link is https://cdsco.gov.in/opencms/opencms/en/PvPI/  . You can also refer to more PV dedicated link which is PVPI (Pharmacovigilance Programme of India) https://ipc.gov.in//PvPI/pv_home.html 


1.5) UMC-  Uppsala monitoring centre based in Sweden is an independent, not profit foundation and is headquarters for all PV activities. It is the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring. UMC operates the technical and scientific aspects of the WHO’s worldwide pharmacovigilance network. They have number of courses available (online,conference,workshop) and huge number of articles from UMC,WHO and Scientific publications.

1. 6) ICH website- The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration and has published guidelines that remain to be accepted by almost all regulatory agencies especially the key one’s e.g. US, Japan and EU.  And this are basis to national PV guidelines of many countries.
All required documents and guidelines like ICH E2A, ICH E2B etc are freely available for download.

2) Miscellaneous
There are number of other sources to read about PV such as  blogs, website,institutes, pharma companies, journals.  They do provide good content, good training and learning course materials. I have mentioned few of them, but does this should  not be taken as my personal endorsement (I have no invested profit interest in them).


2.1) DSRU: This institute provides paid training courses in Europe mostly, check out website the courses appear very well designed and informative. But they appear to be bit costly.The advantage is to go for diploma and masters and with online course availability, they have done a good job.

2.2) EU2P: This offers courses mainly on European regulations. The courses are available on variety of topic and the scores can be collected to qualify for diploma, masters or certificate course. They have online learning option.

2.3) ISOP : International society of pharmacovigilance also offers courses and training materials. They also arrange events and conferences. It is beneficial to take their membership and they offer reduced membership fee for low income countries and students etc.
From https://www.urbanpro.com/a/6-tips-efficient-online-learning


2.4) Online portals: Many other company owned websites  host lot of updates on pharma domain news like pharmabiz, pharmatutor, Fierce pharma-http://www.fiercepharma.com/, They are more like online newspaper.

2.5) Blogs : There are not many blogs that I found useful talking only about PV. However many CRO’s post PV topics on their company blog, where they ask their PV experts to write articles on PV topics, this is worth reading and following.


2.6) Social media: I do not know much about Facebook, except few PV dedicated pages but they post only job listings, but Linkedin is very good tool to keep in touch with domain knowledge, there are many PV groups that you can join where articles on PV topics are posted like Pharamcovigilance professionals, Drug Safety, Medical Affairs, Pharmacovigilance experts, PV India, clinical trial group etc.

2.7) Youtube: This is good for people who prefer video content. Few listed below.

https://www.youtube.com/watch?v=Ww75dFrhEYs
https://www.youtube.com/watch?v=z2lU_TGhSDE


Thanks you for going through this exhaustive list, which is just a small effort from my side to share the knowledge.  If you know any other good sources, I will be happy to take a note of same.

Written by
Dr.Shraddha Bhange.
Connect with me Via comments below.
Support the cause of better rural education with me: ThinkSharp Foundation http://thinksharpfoundation.org/#home
(Images are taken directly from Google).


Saturday 6 July 2019

Artificial Intelligence – exciting tool for Pharmacovigilance professionals



The processes involved in the pharmacovigilance (PV) will be improved  by Artificial Intelligence (AI), in near future and AI will be a key player in  making PV processes faster, better and effective.
 AI governed PV processes easily meets compliance, and are much easier and effective for pharma companies and they drastically reduce the cost of running PV process. 

As an example, to showcase how AI is critical player in PV and how it practically affects all PV process, I am presenting one example below. To make things simple to understand, I have taken example of Literature review to showcase how AI helps in PV process.
AI is making literature review and its validation process very easy and automated with  reduced human  efforts.

Literature Review Process in PV:

What is Literature review?
All Pharma companies need to search, analyse and review world-wide published literature for all   there medicinal products . Followed by making decisions regarding creation of  case reports from such articles that needs to be databased as Individuals case safety reports (ICSRs). This ICSR/Case reports are literature articles that are describing safety related issues occurring in a patients taking particular type of drug products, in laymen’s term “side effect reports or articles”.
.
Why do we need to do literature review?

The medical literature is a significant source of information for the monitoring of the safety profile and maintaining the risk-benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues. Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline or Embase) no less frequently than twice a month preferably once a week. It is mandatory activity by health authorities worldwide for pharma companies.


Challenges in manual/current literature review process:
The literature reading and identifying the valid ICSRs is very boring and tedious work and most of the time error and non-compliance by employee is major challenge faced by pharma companies. This adds to time spent by employee, financial expenses, and efforts to run the process in complaint manner.



Quantity of task: When we do search and download the literature articles from Embase (major source of literature downloads and is widely used) for a medicinal product, search results gives us thousands of literature articles for our product. The ratios of valid safety information containing articles/ ICSR out of this 1000 articles is  merely 5-10 maximum relevant articles.


Quality of task and time spent: To identify these 5-10 relevant articles/valid ICSRs we have to read these 1000 ICSRs which is very time consuming, costly and a process that has loopholes for noncompliance. To give an idea per day an experienced PV professional read 100-150 articles and identifies valid ICSR’s. Out of this Valid ICSRs there are few ICSRs that has timeline of 15 days from its receipt’s. This adds to the effort and compliance.

How AI can help in literature review process :
What is AI?
In simple terms, AI technology works on logical process and commands given to it while developing it to provide results or do task as required.
The definition of AI from the internet is “ is the simulation of human intelligence processes by machines, especially computer systems. These processes include learning (the acquisition of information and rules for using the information), reasoning (using rules to reach approximate or definite conclusions) and self-correction”.

How AI will work in literature review?
When  we train  AI tool about Literature selection criteria for a particular medicinal product to do literature search, it runs its program with this preset combination and provides us the valid safety information articles out of 1000 non-relevant articles within one click.
AI tool also has a capability to learn, when we run 1000’s of literature article with the help of  AI tool it starts learning and becomes more  accurate and effective with time.
As AI is technology which learns and adapts, once we set it to recognize the safety information it effectively becomes faster and better than manually reading and scanning 1000 of literature articles. This will save time and efforts, which can be utilised to review and analyse only those articles that are relevant by PV professionals.
The regulatory compliance and time lines are meet even with the small team of employees working in PV once AI is implemented. AI can deliver the best quality output and to reduce the time and human efforts. It reduces the cost positively affects the price of medicines, the goal is to make medicine affordable and easily available to all patients.

Challenges of AI:
 AI has its own set of challenges, one of it is a  AI development which requires best IT technical skill as well as core expertise in  Pharmacovigilance to implement the set of instruction in AI tool.
I personally know about an exciting start-up company, which has developed AI tool, which is much powerful and can replace the traditional process in Pharmacovigilance, I am more than happy to share more details regarding same, contact me for more details about the same on my email id darshit_dra@yahoo.in.

Written by
Darshit Patel

Edited by 
Dr.Shraddha Bhange

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