Recent changes or scenario's in PV due to Corona Pandemic

The world is struggling with COVID-19 pandemic situation and hence healthcare and pharma industry has taken the centre stage. Everybody is looking towards our industry to find a solution for this pandemic. And yes , our industry is doing its best, new vaccines are being looked at, faster tests to identify the virus is being worked on, alternative treatments are investigated. Off course with this new and old treatments being investigated, ensuring they are safe and effective is critical. It is now more important that pharmacovigilance activities should tbe discussed and implemented more critically.

So what are the challenges, solutions and changes that have been taking in PV due COVID -19?

It is impossible to enumerate or follow all the new regulations or news related to this topic, i have tried to list few that i have found and seemed important below:

1. MedDRA :(Reference link below)

MedDRA released its version 23.0 recently to add terms related to COVID-19. This updated terms are available in excel to be downloaded . A quick glance at excel, i could see 83 LLTs are added.

However the SMQ's are not updated (i.e. Infective pneumonia and SMQ Opportunistic infections) which will be impacted by COVID-19 terms, what i understand from this is, if we are using SMQ's to run linelisting for COVID-19, the AEs will not be populated in that SOC's.

MedDRA has decided to soon launch a dedicated SMQ for COVID-19 in version 23.1.

2. Regulatory submission timelines for ICSRs:(reference links below):

Almost all HA (health authorities) are providing flexibility to MAH (marketing authorization holder) to submit ICSR (individual case safety reports) as per priority. HA's acknowledges there could be reduced workforce and other operational challenges faced by MAHs. They do not discourage reporting AEs on time and as per pre pandemic processes if possible, but in case its not possible, they have released detailed guidelines.

I have enlisted 2 main HAs as an example, EMA and FDA.

EMA enlist prioritizing as below: 

1. Serious ICSR related to COVID19 products

2.Other serious ICSR

3.Non serious ICSR related to COVID19 products

4.Other Non serious ICSR

To note lack of effect AE associated with COVID-19 treatment medications will be expedited to be submitted within 15 days as it LT disease.

FDA has also taken same stand as in, they have said to prioritize reporting of AE related to COVID-19 first. All other AEs if can be reported in same possible way by MAH , it should be, however if not possible, they should be stored and reported as per time lines within 6 months to FDA .

3. Treatment emergent AEs (reference links below)

 Medications that are approved for other indications are being used for treating COVID-19 . I have enlisted few of them below. So the ICSR's and other PV documents for this medications might increase. Clinical trials are also underway for same, for the new COVID-19 indication.

1.hydroxychloroquine 
2. lopinavir/ritonavir

For example, for hydroxychloroquine which is approved as anti malarial but being indicated for treatment of COVID-19, there was already established risk of QT-prolongation, but as this is being used at higher dose than as antimalarial the risk might have increased . This should be monitored and hence ICSR management and safety monitoring will increase for such medications.

Other drugs that are being used for  COVID-19 treatment are but not limited to other antivirals -oseltamivir, ribavarin, antibacterials - amoxicillin/clavulanate, azithromycin, ceftriaxone, vancomycin and anti-inflammatories/other drugs -methylprednisolone, mucinex etc.

4.  Changes by HA for faster development of treatment:

Every HA, Pharma companies and even common man, all are waiting andworking hard to find a treatment for COVID-19. To make treatment available as fast as we can, many HA have taken measures to reduce the wait time in approval process.

As an example, EMA has released a guidance where they are providing flexibilty to MAH by making the submission of application for potential treatments free of charge, without submission deadlines and the EMA will process application in short time of only 20 days.

FDA also has released a fast track approval program Coronavirus Treatment Acceleration Program (CTAP), where FDA will ensure faster application review of COVID-19 treatment developers, as early as 24 hours.

Also the conduct of clinical trials for the new treatment will significantly be different, hence ensuring the safety and following PV guideline is very critical. The top 5 vaccines in race are enlisted below. 

1.The SARS-CoV-2 mRNA-1273 by moderna 

2.Ad5-nCoV vaccine by CanSino Biologics

3.ChAdOx1 by University of Oxford

4. DNA vaccine by Inovio Pharmaceuticals

5.Inactivated SARS-CoV-2 by Sinovac Biotech

5. Other operational changes:

The conduct of clinical trials, GMP,GCP,GDP and other such guidelines for other products have also been revised.

Due to social distancing, lockdown, travel bans and such the standard processes in PV are affected.

For example conduct of audit and inspections will be virtual. Risk communication measures to HCP from MAH will be more via social media channels.

There are many other changes and challenges and or revised guidelines that will impact PV (cannot enlist all to limit length of blog), if you know more, please share in comments.

Reference:

https://www.meddra.org/covid-19-information-page

https://ec.europa.eu/health/sites/health/files/human-use/docs/guidance_regulatory_covid19_en.pdf

https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/detailed-guidance-icsrs-context-covid-19-validity-coding-icsrs_en.pdf

https://www.fda.gov/media/72498/download

https://www.raps.org/news-and-articles/news-articles/2020/3/fda-revamps-adverse-event-reporting-guidance-for-c

https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/guidance-medicine-developers-companies-covid-19

https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap

https://www.the-scientist.com/news-opinion/covid-19-vaccine-frontrunners-67382

Written by:

Dr.shraddha Bhange.

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Adverse Event, reaction and serious AE_definitions and discussion

Many a times when I interview fresher candidates for pharmacovigilance domain, I discuss if they know difference between adverse event, serious adverse event and adverse drug reaction.  They seem to just mug up the definition, i.e know it from internet but when told to explain it, they fail, meaning no understanding of concept. In fact even though experienced professional seems to know it, we often forget the concept and remember the definitions only.

This is what i call the gap between understanding concept and knowing a concept.

Lets discuss terminologies AE,SAE and ADR  as an example and there definitions from three regulatory guidelines where definitions varies but concept remains same . It is important to understand concept rather than just knowing  the definition. 

I have copied the definitions from various guidelines for discussion (Link below).

                                                           

Adverse Event (or Adverse Experience): Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

In the above definition it is important to understand that they are talking about "untoward medical occurrence" hence if we have an reporter who reported an unexpected beneficial effect of the product which is not untoward, where would it be classified ? We will still capture it as AE but it will be discussed in "Benefit analysis" too.

Also point to remember , it says medical occurrence,so not only it can be an event but also an outcome, hence even when only death is reported we capture it as AE.

Adverse Drug Reaction (ADR) : (Definition for Clinical Trials)_all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.

Here. it is important to remember , it says at any dose, so we capture overdose, misuse, missed dose, underdose as AE's too. If we remember and understand this concept it is easy to understand the special scenarios as above and why they are captured as AEs.

Adverse Drug Reaction (ADR) : (Definition for Post Marketing)_ A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.

Here it specifies AE's are captured for any product be it a drug ,vaccine or device which are used not only as treatment but for prevention or even modification of physiological function.

Serious Adverse Event or Adverse Drug Reaction:

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: * results in death, * is life-threatening, *  requires inpatient hospitalisation or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, or * is a congenital anomaly/birth defect.

The basic concept people often forget or confuse is life threatening and also congenital anomaly or defect. It is always a good idea to read about it in guidelines.

To add, lets also correlate, compare and see the definitions from GVP module annex I (Link below).

AE: Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Additionally GVP is helpful as it clarifies more as below:

An adverse event can be an abnormal laboratory finding, hence we capture AST/ALT increased as AE even if they are asymptomatic,  adverse event can be an symptom, hence we capture stand alone fever,nausea,vomiting as events despite knowing they can sometimes be captured as standalone diagnosis or they may not have a diagnosis, or  adverse event can be an disease temporally associated with the use of a medicinal product.

UMC (Uppsala Monitoring Centre) (Link below) also provides definitions described below. They also convey the same meaning, hence the concept remains same, but understanding it and knowing them all together is critical so as to apply it in daily operations.

One interesting point is UMC also defines adverse effect. Hence we can now see, why we capture lack of effect cases as well!

Adverse drug reaction (ADR): A harmful effect suspected to be caused by a drug.

Adverse effect: A negative or harmful patient outcome that seems to be associated with treatment, including there being no effect at all.

Adverse event: Any negative or harmful occurrence that takes place during treatment, that may or may not be associated with a medicine

References:

ICH E2A: https://database.ich.org/sites/default/files/E2A_Guideline.pdf

GVP Annx I: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-annex-i-definitions-rev-4_en.pdf

UMC : https://www.who-umc.org/global-pharmacovigilance/publications/glossary/

Written by:

Dr.shraddha Bhange.

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

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