Pharmacovigilance(PV) is not a cost center its a cost saving centre

                                Pharmacovigilance(PV) is not a cost center its a cost saving center

If you have worked in mid to senior roles in PV, you may have across this dilemma where we need to continuously convince, communicate and influence other non pharmacovigilance departments regarding the importance of pharmacovigilance. And the more difficult task for someone in leadership is to also break the myth that "PV is a cost center" meaning PV does not bring any money and on contrary we have to invest the money in running the pharmacovigilance department. 

And the basis of this argument, is actually coming from the fact that, pharmacovigilance requires setting up the call center (toll free number, telephony and employees working 24/7 to handle the calls), then collection of adverse event via other sources, safety database (very costly licenses), and other application supporting safety database, costly aggregate reporting applications, signal detection applications, so on and so forth. All this applications need to be validated and upgraded every time, hence this is never ending payments to the application owners. Also its a niche area so the human resource have to be highly trained and experts (pharmacists, doctors) so this also adds to cost. Moreover the inspection and audits add to the cost. So what people perceive does have the basis?  Owing to all of this factors, there is always an ongoing struggle to get more budget and investment for pharmacovigilance related assignments in PV department.

How do we change this perception? No definite or one size fits all answer. But one thing we can do is to convert our data that we analyze and the outcomes we generate from this data into meaningful and relevant easy to understand impact and value we create for patients.

This are thinking points for each person working in pharmacovigilance and not for the department heads, because as a working professional even when we work as data entry, we need to know the value and impact and importance of our own PV work we do. Additionally we need to prepared to also spread the awareness and message to others whenever needed.

Key components that can be used for building our case

1. Regulatory expectations: 

Understanding and complying to the regulatory guidance is not an easy task. While the regulatory affairs department is the one leading the dialogue and ensuring the compliance, pharmacovigilance is the one who is implementing and ensuring we have documented evidence to showcase our compliance to regulatory authorities. 

Markets the drug is being marketed are covered by that country's pharmacovigilance regulation from national health authorities. Although at high level the PV requirements remains consistent they are changing, evolving and differing at country level This needs to be showcase on how we meet those specific country requirements.

Having a core data available that can be presented regarding the most complex health authorities requirements and how PV meet them with ongoing addition of examples on changes adapted to meet this HA compliance will make it easy for non-PV leadership to also understand importance. E.G. Instead of showcasing we met FDA requirements, add and example that FDA requirements and give example on them how they were met and what was the outcome.

 2. All is well until its not /Inspections

Build and maintain a database on pharmacovigilance inspections done by various regulatory inspections in terms of name of health authority, type of inspection, duration, inspectors, findings and category of each finding, outcome of inspection, what were corrective and preventive actions implemented. Talk about the outcome especially positive how it saved money in terms of not having non compliance.

3. Outsourcing vs inhouse 

The age old dilemma of having a pharmacovigilance department in pharma company or to outsource the PV to CRO/KPO/BPO (Vendors). Both has its own merits. Clear, Definite and Ongoing continuous evolving PHARMA-Vendor model of partnership serves as the best solution. For a pharma company a due diligence on Vendor is must i.e. are the process set, is it working model, what would be cost of implementation, how much oversight will be needed. Ultimately having an actionable plan that can be referenced in terms of the business value the vendor is bringing is must.

4. Data points that can be used

While showcasing the impact and value pharmacovigilance creates, the easiest data points is volumes i.e. how adverse events are received and processes (ICSR volumes), submission compliance ( timelines met to submit to each health authority) how many aggregate reports processed ( PSUR, DSUR, PADERs), how many articles reviews, how many data sources screened for signals, number of signal identified and validated.

The tricky data points that are difficult to put in coherent and relatable manner are what this means for business and patients. For this we need to build stories, if a signal is validated how was it addressed and how it helps patients, if there was a health authority request how was it managed. If there was non required ask by health authority and we could say no and it was accepted e.g. conducting a phase IV study, how much money was saved etc.

Written by:

Dr. Shraddha Bhange.

Connect with me Via comments below. (I do not respond to Facebook/Instagram messages)

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

Clinical Safety

A. Definitions of Clinical Trials:

Clinical trials (CT) are research studies performed to discover new treatments that are safer and more effective for the prevention, detection, or treatment of diseases. In this blog, I have interchangeably used clinical trials and clinical studies.

1. Phase I Trials: For the first time, a small group of people, healthy volunteers (20–80) is tested with an experimental drug or treatment to assess its safety and identify any side effects.

2. Phase II Trials: The experimental drug or treatment is given to a larger group of individuals (100–300) to verify its effectiveness and further assess its safety.

3. Phase III Trials: Large groups of participants, the general population (1,000–3,000) receive the experimental drug or treatment to confirm its efficacy, monitor side effects, compare it to standard treatments, and gather information for the safe use of the experimental drug or treatment.

4. Phase IV Trials: Post-FDA/HA approval and public availability of a drug, researchers continue to monitor its safety, collecting additional information on the drug or treatment's risks, benefits, and best use.

Various other types of definitions are expected to be known and concept understood e.g. interventional studies, observational studies, PASS (Post-authorization safety study), Randomized trials etc.

B. PV-related elements for Clinical 

 1. Design of study: 

The safety team is involved from the beginning of the study i.e. study concept or proof of concept along with other departments such as clinical, medical affairs, marketing, and regulatory. 

Which population needs exclusion based on the data available in terms of risks or data unavailable where we cannot specify or characterize the non-reversible or non-treatable risks i.e. teratogenicity, mutagenicity, etc. Which population will be included based on maximum data generation to understand the benefit-risk profile of drug with minimal patient safety concerns and a cost-effective model. The safety team is also involved in the study milestones i.e. interim report, final study report, etc.

2. Clinical study protocol safety review: Clinical study protocols are the document that will describe the title, aim, methods, monitoring of patients, guidance for investigators for conduct of trials, and primary and secondary outcomes for the study. This document needs to be reviewed by the pharmacovigilance/safety team. The sections in the protocol about the study concept in itself e.g. is this the correct population for the study outcomes, are there any restrictions due to safety reasons, which SAE will be expected. Instructions for the investigators on identification, treatment, and prevention of known SAE associated during the study conduct will be reviewed by the safety team.

 3. Informed consent form (ICF): This is a document that is signed by the clinical trial participants and describes the risks associated with being in the CT. This document is prepared by the clinical team; however, it is reviewed by the pharmacovigilance/safety team. This document is designed in a very simple form so that layperson/common man/nonscientific person should understand. Each adverse event added in the ICF should be simplified and the usage of signs and symptoms is preferred to diagnosis as patients/participants will be able to identify them easily. The safety team has to ensure the adverse events are addressed appropriately as per the current safety profile of the drug. 

4. Clinical study report submission: The interim study report and final study report are major milestones where the safety team will also review the study report in terms of the presentation of adverse events and the conclusion on the safety of the product. 

5. MA application based on study and safety involvement: 

The marketing authorization dossier requirements are complex and varied across regulatory agencies. One critical and consistent requirement is the presentation of data and its analysis with a conclusion on the positive benefit and safety of the product. The clinical data from the study has to be reviewed by safety and its analysis based on the seriousness, severity, reversibility, and treatability of the adverse events described and then categorized and characterized into risks.

6. Scientific elements 

While preparing, conducting, and concluding clinical trials there are key scientific principles that are expected from a safety team to be aware of.

1. Pregnancy prevention:

Classification of the investigational drug if it fits the profile of teratogen or genotoxic if yes, then how will the study team ensure pregnancy is prevented. The contraception methods and duration of contraception must be described. if pregnancy occurs how it will be addressed. Usually, this means termination from the study if they choose to continue it. If the product is not teratogen or genotoxic, pregnancy can be allowed and subject can still be in trials but this will depend on study indication and if benefits outweighs risk to remain in study. Regardless of pregnant subject staying or discontinuing from study, she will be follow up to document the outcome of pregnancy . 

2. Hepatic, renal and cardiac monitoring:

Pragmatic monitoring of hepatic, renal and cardiac values instead of stringent baseline values has become acceptable. As liver diseases become common due to other diseases leading to liver dysfunction, patients recruited in clinical trials have already dysfunctional liver profiles at baseline. Even for kidney function tests choosing the right lab parameter to monitor i.e. instead of low GFR, sustained lower decline in GFR is more noteworthy to monitor in patients with kidney diseases. Cardiac functions are also important to be monitored as with more and more populations having some preexisitng cardiac dysfunction, excluding them is not the best outcome. So the organ toxicity identification and treatment has to be based on a baseline that considers this preexisting medical history and dysfunction. The duration of monitoring liver, renal, or cardiac enzymes, mechanism of action of the drug, study indication, and other risk factors should be considered when the safety team reviews and includes the about identification, monitoring, and treatment of liver dysfunction. Parameters and their clinical relevance for monitoring like AST, ALT, AST: ALT ratio, Serum bilirubin, GFR, Troponin, ECG Ultrasound are chosen in a way that makes the most efficient results when it comes to early identification and treatment for patients.

 

References:

1. FDA Website

2. Stanford Clinical trials

3. Treem, W.R., Palmer, M., Lonjon-Domanec, I. et al. Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis. Drug Saf 44, 133–165 (2021). https://doi.org/10.1007/s40264-020-01014-2

4. International consensus definitions of clinical trial outcomes for kidney failure: 2020Adeera Levin ,Rajiv Agarwal,William G. Herrington,Charu Malik, Vlado PerkovicInternational Society of Nephrology’s 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials

 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