Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem. The European Medicines Agency (EMA) coordinates the European Union (EU) pharmacovigilance system and sets rules and guidelines to ensure the safety of medicines marketed in the EU. As per EU law, each marketing authorization holder (MAH), national competent authority, and EMA is required to have a pharmacovigilance system in place such that the use of medicines post their approval is monitored in healthcare practice and adverse effects and safety risks are caught as soon as they occur thereby minimizing the number of exposed patients.

The EMA requires the operation of pharmacovigilance practices throughout the product lifecycle. The EudraVigilance system which is a central electronic database of adverse events is in operation throughout the product lifecycle including research and development, marketing authorization and post-authorization phases and includes activities such as safety monitoring, signal detection, risk assessment, and regulatory decision-making. Risk management plans that outline the medicine’s safety profile and assessment of the risk-benefit ratio are necessary during the marketing authorization and post-authorization phases and are mandatory to be submitted. The post-authorization phase includes several pharmacovigilance activities such European Risk Management Strategy (ERMS), adherence to Good pharmacovigilance practices (GVP), incident management plans, medical literature monitoring, medication errors, periodic safety update reports (PSURs), pharmacovigilance systems, post-authorization safety studies, and signal management.

Figure 1 shows the key regulations applicable to pharmacovigilance in for medicines marketed in the EU:

Regulation (EC) No. 726/2004

This involves union procedures for the authorization, supervision, and pharmacovigilance of medicinal products for human and veterinary use. It highlights the role of the Pharmacovigilance Risk Assessment Committee (PRAC) for conduct of pharmacovigilance tasks and approval and monitoring of risk management systems. In the context of pharmacovigilance activities, it states mandatory requirements by marketing authorization holders on the continuous monitoring of medicines and post approval safety studies.

Directive 2001/83/EC

This covers the legal framework for authorization, supervision, and pharmacovigilance of medicinal products for human use in the EU. It emphasizes the importance of continuous adaption of pharmacovigilance systems, accordance with international guidelines, and on-going pharmacovigilance activities. Various pharmacovigilance activities such as adverse event reporting, risk management plans (RMPs), periodic safety update reports (PSURs), pharmacovigilance system master file (PSMF), and signal detection and management are described and should be available.

Regulation (EU) No. 1235/2010

This is related to pharmacovigilance activities for the supervision of medicinal products including RMPs, PSURs, inspections, signal detection and evaluation, ICSRs and electronic reporting, and PSMF.

Regulation (EU) No. 520/2012

This is related to the performance of pharmacovigilance activities and includes information on the content of PSMF and quality systems, information for monitoring of data in the Eudravigilance database, the signal management process, and details on the content of ICSRs and PSURs.
In November 2023, the EMA published an updated guidance on post-authorisation procedural advice for users of the centralised process which covered topics such as post-authorisation procedural advice, guidance documents and templates, pharmacovigilance activities, product information updates and timelines for submission of various activities. With respect to pharmacovigilance activities, information on changes to quality systems and PSMFs and intimation of authorities of these changes, details on pharmacovigilance system inspections, scientific advice and proactive pharmacovigilance planning procedures, submission of pharmacovigilance reports and interim reports, and additional pharmacovigilance activities are described. Guidance on post-authorization safety studies (PASS) and post-authorization efficacy studies (PAES) are also available in this guidance.

Other recent updates to pharmacovigilance activities in the EMA include

• Inclusion of real-world evidence (RWE) is emerging for the assessment of the safety of medicines in real-world settings through examination of registries and electronic health records (EHRs) and is being integrated into pharmacovigilance practices.
• Good pharmacovigilance practices (GVP) are a set of measures drawn up to facilitate the performance of safety monitoring of medicines in the EU. GVP guidelines are continuously updated to reflect changes in regulatory guidelines and advancements in safety management techniques. In 2020, GVP were modified to include requirements for submitting information on non-interventional post-authorization safety studies and inclusion of methodologies, criteria, and approaches for assessing the effectiveness of risk minimization methods.
• Electronic reporting of ICSRs and adverse effects is encouraged as it allows for submission in a standardized format facilitating information sharing, regulatory activities., and timely decision-making. Submission processes, controlled terminology, and integration with data sources are continuously changed and updated to comply with Eudravigilance databases. Latest updates to Eudravigilance system in 2022 include alignment with Substance, Product, Organization, and Referential (SPOR) data services to standardize terminologies and identifiers in data entry thereby streamlining data exchange across different stakeholders and formats.

Therefore, although the EMA has a robust system in place for pharmacovigilance activities, continuous changes and updates are inevitable and should be considered for realizing the full benefits of pharmacovigilance systems. It is important to think of pharmacovigilance as a work in progress as new data entry systems, data sources, and formats are dynamic.

Read More: Digital Health Technologies in Pharmacovigilance

References

1)     EudraVigilance: electronic reporting | European Medicines Agency (europa.eu)

2)     Archive of development of good pharmacovigilance practices | European Medicines Agency (europa.eu)

3)     Pharmacovigilance: Overview | European Medicines Agency (europa.eu)

4)     EUR-Lex – 32004R0726 – EN – EUR-Lex (europa.eu)

5)     Microsoft Word – Human Code.doc (europa.eu)

6)     Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal productsText with EEA relevance (europa.eu)

Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects and other drug-related problems. It is an important component of the post-marketing surveillance program of medicinal products and medical devices as it helps monitor adverse effects (AE), adverse drug reactions (ADR), and any other safety concerns that were not captured during clinical trials. Safety data from pharmacovigilance activities is critical as it gives information about the benefits/side effects of the drug in a diverse patient population and helps detect any new and previously unreported risks. Although several pharmacovigilance systems are in place and most companies employ pharmacovigilance activities, it is often possible to miss some important safety information and underreporting is common. The FDA pharmacovigilance systems voluntary reporting systems such as MedWatch for consumers and healthcare professionals and VigiBase used by the World Health Organization (WHO), reporting by sponsors, and mandatory reporting by manufacturers involves data collection to the FDA Adverse Event Reporting Systems (FAERS) database which then reaches the FDA to make decisions on new warning labels or withdrawal/limited use of the product in the market.

Although pharmaceutical manufacturers, sponsors, and patient advocacy groups have realized the importance of good pharmacovigilance practices, pharmacovigilance activities and reporting continue to remain plagued by challenges. Underreporting, misreporting, missing and incomplete information, and inconsistences in safety data are considered common as they are entered into systems both voluntarily and in a non-standardized manner. Analysis of trends and patterns from a large volume of data is also difficult if not handled by advanced analytical techniques to draw meaningful conclusions. Thus, digital health technologies (DHT) are an important tool to improve pharmacovigilance by enabling collection and analysis of adverse events and safety data.

Digital health technologies (DHT) use computing platforms, connectivity, software, and sensors for healthcare and related uses. They include mobile medical apps (mHealth), artificial intelligence (AI), and machine learning (ML), wearable devices, telehealth and telemedicine, and personalized medicine. 

There are two major ways in which DHTs are applicable in pharmacovigilance as shown in the Figure below:

Figure. Impact of DHT on Pharmacovigilance

Data collection

Wearable devices

DHTs such wearable devices including mobile phones, smart watches, fitness trackers, and mobile apps involve real-time collection and monitoring of data allowing adverse events to be detected, identified, and categorized as soon as they occur. This allows regulatory authorities and manufacturers to take immediate action and mitigate any potential risks.

Online platforms and social media

Online communities and social media websites serve as an important repository of safety concerns and information that are entered in by patients, advocacy groups, and caretakers. This information is important as it is entered directly in by patients and can help identify trends in safety data for certain drug classes and medical devices.

Electronic health records (EHRs)

EHRs are an important source of data for detection of adverse drug reactions and allow for cross-functional sharing of information with network of healthcare professionals enabling tracking and remediation of safety information. EHRs contain more detailed information such as timing of medication administration, symptom development, and detailed clinical history which may be of interest in understanding adverse events in a comprehensive manner.

Telemedicine

Telehealth platforms which involve remote visits and monitoring of patients without the need for in-person consultations are important for identification and communication of safety concerns by patients in a timely manner. This method allows physicians to understand adverse events and take appropriate adjustments such as stoppage of medication or dosage adjustments and can be integrated with EHRs.

Data analysis

Artificial intelligence (AI) and machine learning (ML)

These technologies serve to go through large amounts of data generated from wearable devices and process it to identify trends and patterns in safety data. AI allows for processing of pharmacovigilance reports and signal detection to extract information about potential adverse drug events. Data mining and prediction using AI and ML is also done on data obtained from social media platforms. ML techniques can be used to predict the probability of developing an adverse event based on patient history and characteristics and helps in the development of predictive models.

Data integration

Technologies such as AI and cloud computing are important in the field of pharmacovigilance which involves data extraction and analysis from a wide variety of sources into a single dataset to identify trends in safety information. These technologies are also important in ensuring data security and privacy.

Natural Language Processing (NLP)

This system helps extract structured safety and adverse event information from text-based documents such as EHRs, narrative reviews, and social media platforms. 

Big data analytics

This is important for processing vast amounts of data and uses algorithms to extract meaningful insights regarding safety concerns linked to use of drugs or medical devices. It involves integration of diverse data form different sources to ascertain the causes of adverse events and is particularly useful when the data comes from unstructured sources such as (real-world evidence) RWE studies.

Therefore, application of DHT is a vital component of pharmacovigilance practices allowing more data to be handled in an accurate and timely manner which facilitating results in safety information to be identified rapidly and swift action by regulatory authorities to safeguard patient health.

Read More:  Pharmacovigilance (PV) Services at a Glance

References

1. What is Digital Health? | FDA
2. Pharmacovigilance Analytics – Pharmacovigilance Analytics
3. Natural Language Processing for EHR-Based Pharmacovigilance: A Structured Review – PubMed (nih.gov)
4. Transforming Drug Safety: The Future of Pharmacovigilance and Technology (pharmaceuticalcommerce.com)

Ensuring the safety and efficacy of new drugs, medical devices, and biological products does not end once the treatment is approved or is on the market but extends to the post-marketing phase. Since the overarching goal of all new approvals is to advance therapies for certain diseases and conditions in a safe manner, pharmacovigilance activities occupy a vital role in the product lifecycle.

Pharmacovigilance (PV) refers to the science and activities related to the detection, assessment, understanding, and prevention of adverse events or any drug-related safety problems. By monitoring safety signals and adverse events associated with health products, sponsors and regulatory authorities can decide on the fate of the products and thereby safeguard the health of patients and maintain public health. Various PV activities are essential in characterizing the risk-benefit profile of products and are necessary to be submitted to regulatory authorities as part of ongoing programs both during development and after marketing approval (Figure 1).

Figure 1. Pharmacovigilance (PV) activities during product lifecycle

Periodic safety update report (PSUR)

A PSUR is a comprehensive document that provides a detailed analysis of the safety profile of a drug product and is required by regulatory authorities at define time points after marketing authorization. It collates safety information from various sources and presents the risk-benefit profile of the product to regulatory authorities that ultimately determine the fate of the product and the need for further investigations into its safety.

ProRelix Research can help conduct the following activities for the development of PSURs for your product:

• Comprehensive search to identify safety information from various sources such as clinical trials, registries, post-marketing data, and literature sources
• Submission of PSURs to regulatory authorities as per predefined timelines post-marketing of the product
• Development of PSURs as per the content required for a particular regulatory authority
• Statistical analysis and data mining for individual case safety reports (ICSRs) to asses and analyse signals
• Development, assessment, and periodic review of risk management plans and risk minimization strategies
• Provide responses to regulatory agencies and submit any additional information required

Pharmacovigilance System Master File (PVSMF)

The PVSMF provides information about the organization, processes, procedures, and responsibilities related to the collection, assessment, and reporting of adverse drug reactions (ADRs) and drug-related safety information. It is essentially an overview of the PV system of the sponsor and ensure safe use of the product.

We can help develop a PVSMF for your drug product as per regulatory authority guidelines by assisting with the following:

• Content development for a PVSMF including details such as organization and personnel, PV activities, quality management, safety databases, training and education, and regulatory authority communications and meetings
• Regular and periodic updates to PVSMF in accordance with organizational and regulations changes
• Preparation of PVSMF for inspection and audits by regulatory authorities

Pharmacovigilance (PV) plan

A PV plan is developed by a sponsor prior to the products market approval and contains the strategies, processes, and activities that will be used to ensure safety monitoring including detection, assessment, and management of ADRs and safety concerns.

A comprehensive PV plan is critical and should be developed with care. ProRelix research can support with development of a customized PV plan with the following features:

• Development of a risk management plan including risk identification, evaluation, and minimization
• Creation of safety data collection methods including ADR reporting, case processing, development of PSURs, and data analysis
• Assistance with development of processes for signal detection such as review of ICSRs, data mining of safety databases, literature monitoring
• Preparation of safety dissemination information such as educational materials, changes to product labelling, and safety alerts
• Communication and updating regulatory authorities on changes to PV plans

Standard Operating Procedures (SOPs)

Pharmacovigilance SOPs provide a detailed written instruction on steps, processes, and protocols necessary for carrying out various PV activities. SOPs ensure consistency and uniformity in performance of PV activities as per regulatory requirements.

We help in the development of SOPs to achieve your PV goals that are aligned with internal company processes and regulatory requirements for various activities such as:

• Adverse event reporting and processing
• Safety surveillance and monitoring
• Signal detection and management
• Risk assessment and risk minimization strategies
• Safety information dissemination and communication
• PV agreements
• PV Quality management systems (QMS)
• PV inspections and audits

Case processing

Case processing involves the systematic and standardized handling of ICSRs and allows for the detection of new safety concerns and ongoing evaluations of benefit-risk profiles of a product. It includes assessment, documentation, and communication of safety data.

ProRelix Research can help with the different steps involved in case processing such as:

• Categorization of ICSRs from various sources based on seriousness and quality
• Support with data entry into safety management systems including vital patient and safety event information
• Thorough quality review process for assessment of data accuracy and completion
• Causality assessment and degree of serious of the AE
• Help in coding of adverse events using standardization dictionaries such as Medical Dictionary for Regulatory Activities (MedRA)
• Comoilation and submission of ICSRs to regulatory authorities
• Development of case narratives
• Archiving and maintenance of case processing activities

Safety database

A PV safety database is a central repository of ICSRs and must be created in accordance with regulatory guidelines. It serves as an accurate and secure source of safety data for a product and provide information on safety signals for risk-benefit analysis.

ProRelix Research can help in the development of a reliable and secure database for your product through the following services:

• Assistance in database design and structure that helps to capture and store relevant safety signals and information
• Creation of validation checks and systems to minimize problems with data entry
• Utilization and integration of coding systems such as MedRA into the safety database
• Inclusion of data security, access controls, and encryption measures to prevent unauthorized access to patient information

References

• Pharmacovigilance – an overview | ScienceDirect Topics
• E 2 E Pharmacovigilance Planning (Pvp) (europa.eu)
• E2E Pharmacovigilance Planning | FDA

3GuidanceBioloGicalProducts.pdf (cdsco.gov.in)

Pharmacovigilance is defined by the World Health Organization (WHO) as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse events or any other drug-related problems.” Drug pharmacovigilance programs form an important part of post-marketing risk assessment and are a part of the Food and Drug Administration’s guidance on risk management activities which include the following:

• Premarketing Risk Assessment (Premarketing Guidance)
• Development and Use of Risk Minimization Action Plans (RiskMAP Guidance)
• Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance)

The reason why the development of appropriate and thorough pharmacovigilance plans is important is that it is impossible to capture all adverse events and safety concerns related to a drug or medical device during clinical trials that are conducted for regulatory approval. Clinical trials are carried out in patients with homogeneous characteristics under strict protocols and monitoring programs. Following regulatory approval, drugs, and medical devices are used in much larger patient populations that differ in terms of their demographic characteristics and medical conditions and which can result in safety concerns that usually do not arise or are not captured during clinical trials. Evaluation of risk-benefit information that becomes available once the product is marketed is necessary to ensure its safe use and reduce risk to patients by allowing feedback to reach users in a timely manner. Therefore, the industry and regulatory authorities are heavily focused on developing pharmacovigilance plans and safety specifications even before the drug or medical device is approved or licensed for use.

Pharmacovigilance programs involve the identification and evaluation of safety signals which refer to a concern about an excess of adverse events compared to what would be expected to be associated with a product’s use. Case reports, registries, observational studies, preclinical data, and surveys serve as potential sources of safety signals. A very important aspect of a good pharmacovigilance program is good reporting practice to ensure that safety concerns are reported and addressed appropriately. Timely reporting and communication, complete and targeted questionnaires or computer-aided interview technologies, accuracy, follow-up in relation to the seriousness of the adverse event, and confidentiality are important elements of good reporting practices and should be rigorously followed.

The signal management process is a set of steps that are performed to determine if there are any new risks associated with a drug or if there have been any changes to the safety profile of drugs. The figure below represents the stages for an appropriate signal management process as per US FDA guidelines:

 Figure. Signal management process in Pharmacovigilance programs

Signal identification and detection

This step involves proactive searches of safety databases using data mining methods to identify any safety concerns or adverse events associated with a drug. The FDA has the Adverse Event Reporting Systems (FAERS) which includes spontaneous reports and serves as an important resource for individual case reports that are entered in by healthcare professionals, consumers, and pharmaceutical companies. The FDA has also launched the Sentinel system for active reporting of adverse events using data from electronic health records (EHRs), insurance and billing claims, and registries and provides data in real-time. Unlike the FAERS system that relies on voluntary reporting pf adverse events which may not be accurate and in some cases incomplete and biased, the Sentinel system is comprehensive. Both the FAERS and Sentinel databases are widely used in signal detection in pharmacovigilance practices. Other sources of information include observational studies, epidemiological studies, spontaneous reports, and literature searches.

Signal evaluation and prioritization

This steps focuses on understanding the reliability of the signal and determining any causal relationship between the drug and adverse event at the time of occurrence of the adverse event, presence or absence of symptoms without drug exposure, comparison of toxicity with other drugs in the same pharmacological class, and evidence of toxicity from preclinical and observational studies along with alternative reasons for the event. Although there is no definitive classification of causality, the FDA recommends categorization of causality into terms such as probable, possible, or unlikely along with a detailed justification of the classification. The FDA recommends a comprehensive account of events leading to safety concerns associated with medication errors. Data mining methods are applied to characterize and collate data. The safety concerns in case of suspected safety risks should be synthesized from various sources and should include background rate for an event, safety findings from controlled trials, measures of association such as odds ratio from pharmacoepidemiologic studies, and general marketing experience with similar products of the class. The FDA assesses potential safety risk of the signal considering factors such as strength of association between the adverse event and product, consistency of findings across available data sources, biologic plausibility, seriousness of the event, and evidence of dose-response for the effect among others.

Signal investigation and analysis

This step involves a thorough evaluation of the identified safety signal and determination of a causal relationship between the drug and adverse event. Data mining methods, and analytical methods such as odds ratio and Bayesian statistics are used to determine the relationship in the presence of confounding factors.

Signal reporting

Once the FDA has deemed a particular safety signal to pose a risk it is essential for the Agency to take suitable regulatory action which can include a change in labeling, restrictions in its use, or in extreme cases withdrawal of the drug from the market. Reporting to regulatory authorities can also be done directly by patients, healthcare professionals, and consumers through the FAERS database to help protect the well-being of patients and develop risk mitigation strategies.

 The FDA has a robust system and process for identification and reporting of safety signals that is vital to protect patient welfare in the post-marketing stage. It is important for all stakeholders such as patient, physicians, regulators, and care takers to play their role and contribute to the safety of participants through a timely and accurate reporting of signals.

Read More :

Clinical trial market size

Pharmacovigilance Services in cdsco

References

1)      Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment | FDA

2)      Guidance for Industry E2E Pharmacovigilance Planning (fda.gov)

3)      FDA Adverse Event Reporting System (FAERS) Public Dashboard | FDA

4)      FDA’s Sentinel Initiative | FDA