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.

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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.

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DSUR (Developmental Safety Update Report)

 DSUR (Developmental Safety Update Report)

DSUR which is prepared while the product is still in development phase, which stands for Developmental Safety Update Report. We can also call it as a pre-marketing equivalent of a PSUR (Periodic Safety Update report).

Before we go to the core of content and format, first let’s understand what a DSUR is?

DSUR is an internationally harmonized, safety document which covers the safety summary of investigation products during their development or clinical trial phase. This means that all new drugs under development that are currently undergoing a clinical trial must submit a DSUR to the regulatory authorities.

Now you might be wondering, why do we come across DSURs for medicines which are already on the market. There will also be instances where a product is already on the market, but the sponsor/MAH (Marketing Authorization Holder/Pharma Company, wants to further evaluate the drug; for example, for a new dose, new formulation or a new indication that is not covered by the drugs approved marketing status. In that case, the sponsor must submit  DSUR until the clinical trials for a marketed drug are ongoing.

What are the objectives of a DSUR? The purpose of a DSUR is to provide a comprehensive annual analysis  of the safety summary collected during the clinical trial. You may consider the document as a communication to the regulators about adequate monitoring and evaluation of a safety profile of a drug under investigation.

What is the scope of products for a DSUR? A DSUR may be required for any of the following

-          Investigational drugs

-          Investigational Biologicals

-          Investigational Vaccines

-          Combination products under investigation.

 Clinical trials using an investigational drug

 Clinical trials conducted to support changes in the manufacturing process of medicinal products

   Clinical trials conducted using marketed drugs in approved indications

  Therapeutic use of an investigational drug

What is DIBD?: - Developmental international Birthdate (DIBD) – it is the date of first authorization from a regulatory agency to the sponsor to conduct any clinical trial for an investigational product anywhere in the world.

How long is it to be submitted?- A DSUR is to be submitted as long as the clinical trial is ongoing. When submission of an annual report is no longer required in an individual country  or region, the sponsor should indicate that the final DSUR serves as the last annual for the investigational drug in that country or region.

What is the frequency of a DSUR submission?- Usually the DSUR is submitted annually (the frequency may vary occasionally as per national or regional regulatory requirement).  

 The first DSUR should have a data lock point which should be within a year of its DIBD.

Also note that the DSUR is to be submitted to the regulatory authorities within 60 calendar days after the DSUR data lock point.

What is the reference safety document for a DSUR? Unlike PSUR, in case of DSUR the IB i.e. the Investigators Brochure stands as a reference document for the DSUR report.  

The Format and Content is described in International Conference on Harmonization (ICH) guideline E2F.

Each section of DSUR is highlighted in the table below, along with a brief overview of what each section entails.

DSUR	PSUR	Comment for ease of understanding
Part I	Title Page	Information about company, author of DSUR, Reviewers , data period etc
Part II	Executive Summary	Snapshot of DSUR , summary of risk-benefit of product
1	Introduction	-          DIBD and Reporting period -          Details of investigational drug- mechanism of action, therapeutic class, dose, route, and formulation, indication etc
2	Worldwide Marketing Authorization Status	-          Date of first approval -          Indication(s), approved dose(s), and countries where approved, if applicable.
3	Actions Taken In the reporting interval for Safety Reasons	-          Significant safety related actions taken during the reporting period along with reasons for each action. e.g. Regulatory authorities requested hold on clinical trials, withdrawal of product etc
4	Changes to Reference Safety Information	Significant safety-related changes to the Investigators Brochure OR USPI or other such RSI documents within the reporting period.
5	Inventory of clinical trials ongoing and completed during the reporting period	-          Overview of the clinical trials ongoing and completed by the sponsor during the reporting period.
6	Estimated Cumulative Exposure 6.1 Cumulative Subject Exposure in the Development Programme 6.2 Patient Exposure from Marketing Experience	-          Sections 6.1 and 6.2 of the DSUR should provide information on cumulative exposure in clinical trials and the marketed setting, respectively.
7	Data in Line Listings and Summary Tabulations 7.1 Reference Information 7.2 Line Listings of Serious Adverse Reactions During the Reporting Period 7.3 Cumulative Summary Tabulations of Serious Adverse Events	This should present important clinical safety information through line listings (cumulative and reporting period)
8	Significant Findings from Clinical Trials during the Reporting Period - 8.1 Completed Clinical Trials - 8.2 Ongoing Clinical Trials - 8.3 Long-term Follow-up - 8.4 Other Therapeutic Use of Investigational Drug - 8.5 New Safety Data Related to Combination Therapies	-          Each sub section should provide a brief summary of clinically important emerging efficacy and safety findings from clinical trial
9	Safety Findings from Non Interventional Studies	-          Relevant safety information from sponsored or co-sponsored non-interventional studies (e.g. observational studies, epidemiological studies, active surveillance programmes)
10	Other Clinical Trial/Study Safety Information	-          Relevant safety information from any other sponsored or co-sponsored clinical trial/study sources (e.g. results from pooled analyses or meta analyses of randomized clinical trials)
11	Safety Findings from Marketing Experience	-          Applicable in case investigational drug has been approved for marketing in any country -          Should provide a summary of key safety findings that have arisen from marketing experience.
12	Nonclinical Data	-          Major safety findings from non-clinical in vivo and in vitro studies (e.g. carcinogenicity, reproduction or immunotoxicity studies) ongoing or completed during the reporting period.
13	Literature	-          New and significant findings, either published in the scientific literature or available as unpublished manuscripts, relevant to the investigational drug during the reporting period.
14	Other DSURs	-          In case, multiple DSURs are to be prepared for a single investigational drug, this section should summarise significant findings from other DSURs. .
15	Lack of Efficacy	-          Data indicating lack of efficacy for investigational drugs intended to treat serious or life-threatening illnesses (e.g. excess cardiovascular adverse events in a trial of a new antiplatelet drug for acute coronary syndromes)
16	Region-Specific Information	-          The information in this section can be used to comply with national or regional requirements and can be provided in appendices to the DSUR.
17	Late-Breaking Information	-          Important safety findings that arise after the data lock point but while the DSUR is in preparation.
18	Overall Safety Assessment 18.1. Evaluation of the Risks  18.2 Benefit-risk Considerations	-          Concise, integrated evaluation of all new relevant clinical and non-clinical and epidemiological information obtained during the reporting period relative to the previous knowledge of the investigational drug.
19	Summary of Important Risks	-          Concise, cumulative, issue-by-issue list of important identified and potential risks.
20	Conclusions	-          Changes to the previous knowledge or efficacy and safety since the last DSUR.

 To summarize, DSUR is a complex and analytical document that should be utilized to analyze risk and safety profile of product in an ongoing manner.

References:

 1. FDA

2. EMA

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