Pharmacovigilance In Clinical Trials

Clinical trials are an integral part in the development of medical products. It is done to ensure that the product under development will cause benefits to the public and not any fatal, serious or life-threatening conditions. The need for and development of pharmacovigilance was taken into consideration only after the happening of Thalidomide tragedy. Read more to learn about pharmacovigilance in clinical trials, regulatory requirement, pharmacovigilance system and more.

What Is Pharmacovigilance?

Pharmacovigilance is defined as the science and activities which are related to the detection, assessment, understanding and prevention of adverse effects or any other medicine related problems. The occurrence of adverse effects in a clinical trial is inevitable. In fact, trials are conducted not only to find the action of the investigational product but also to analyze the intensity of the adverse effect it brings in and take measures to prevent it or make it less intense.

Regulatory Requirements For Pharmacovigilance In Clinical Trials

Requirements to submit safety reports vary for different regions based on regulatory authority. For FDA, under 21 CFR part 312.32 it is stated that:

The FDA along with all participating investigators must be notified by the sponsor in an IND safety report of potential serious risks from clinical trials or other sources promptly. It should not be later than 15 calendar days after the sponsor determines it as qualified information for reporting under paragraph C mentioned in 21 CFR part 312.32.

The sponsor must identify all previous IND safety reports submitted to FDA regarding a similar suspected adverse reaction. Analyse the importance of current suspected adverse reactions with the previous ones or any other relevant information.

Serious and unexpected suspected adverse reaction: Any serious and unexpected adverse reactions are to be reported by the sponsor. To report an adverse event as a suspected adverse reaction, there must be a causal relationship between the drug and the adverse event.

Other study findings: The sponsor is responsible for reporting the findings from epidemiological studies, pooled analysis of multiple studies or clinical trials that suggest a significant risk to the humans exposed to the drug. This is followed even when the studies are being conducted or not conducted under an IND or by the sponsor.

Animal or in vitro testing findings: The sponsor should report findings from animal or in vitro testing, conducted by or not by a sponsor that propose a significant risk to humans exposed by the drug like the carcinogenicity, mutagenicity, teratogenicity reports or other significant organ toxicity.

An increase in the rate of serious suspected adverse reaction occurrence: The sponsor must report any clinically significant serious suspected adverse reaction occurring at an increased rate which is greater than mentioned in the protocol or investigator’s brochure.

IND safety report submission: The IND safety report should be submitted in narrative format or on FDA Form 3500A or in electronic format which can be processed, reviewed and archived by FDA. Council for International Organizations of Medical Sciences (CIOMS) I form is used instead of FDA Form 3500 A to submit foreign suspected serious adverse reactions. Narrative format is used to submit reports from overall findings/pooled analysis of published or unpublished in-vitro, epidemiological, animal or clinical studies.

Every notification towards FDA must bear prominent identification of its contents, i.e., “IND Safety Report,”. It should be transmitted to the review division in the Center for Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation and Research (CBER) which is responsible for the review of IND. The sponsor, upon request from FDA, should submit to FDA any additional data or information that the agency deems necessary, promptly, but not later than 15 calendar days after request receival.

Fatal unexpected or life threatening suspected adverse reaction reports: FDA must be notified of these types of reaction no later than 7 calendar days after initial receipt of information by the sponsor.

Format and frequency of reporting: The FDA can suggest the sponsor to submit reports in a different format or frequency than that stated under 21 CFR Part 312.32. FDA also allows the sponsor to propose and adopt a different frequency and format if it is allowed by the FDA review Division’s Director.

Marketed drug investigations: The sponsor of a clinical study of an already marketed or an approved drug in the US, which is conducted under an IND will need to submit IND Safety Reports of suspected adverse reactions which are observed in the study whether the study sites are foreign or domestic.

Study endpoints: The sponsor must report study endpoints (like mortality and major morbidity) to the FDA as described under the protocol. However, when there occurs a serious and unexpected adverse event and there is a causal relationship between the drug and the reaction, it must be reported. It is reported as stated in 21 CFR part 312.32 as a serious and unexpected suspected adverse reaction. This is required even though it is the component of study endpoint.

Follow up: The sponsor must investigate all the safety information received as soon as possible. A follow-up IND Safety Report should be submitted as soon as relevant follow-up information is available on the submitted IND Safety Report. Upon a sponsor's investigation, the results shown are that the adverse event which was initially thought to be not reportable is now determined as reportable, must be reported as soon as possible. Such suspected adverse reaction must be reported as an IND Safety Report. It should not be later than 15 calendar days after it is determined to be reportable.

The safety information reporting system from clinical trials as well as marketed products is mandatory. But as mentioned earlier in this section, the regulatory authorities in different nations have different requirements.

Responsibilities Of Pharmacovigilance Team In Clinical Trials

Some of the responsibilities of the pharmacovigilance team in clinical trials is as follows:

• The PV team makes sure that the pharmacovigilance processes are in compliance with the respective regulatory requirements.

• Ensuring the collection, evaluation and reporting of the safety data to the regulators.

• Providing a complete and quick response to any queries arising from the regulatory authorities.

• Provides any other relevant information to the regulatory bodies regarding the benefit risk evaluation.

• Proper conductance of all pharmacovigilance activities and submission of PV documents to the authorities.

• Correct, complete and quality submission of pharmacovigilance data to the respective authorities.

• Must have an overview of the safety profile of the product and emerging safety concerns.

• Developing and implementing the risk management plan.

• Verifying and keeping the Pharmacovigilance System Master File (PSMF) up to date with the current pharmacovigilance systems that are being implemented.

Pharmacovigilance Systems

Every country has a pharmacovigilance system put in place to protect the public as well as the clinical trial subjects, create awareness and communicate among the stakeholders regarding the adverse effects. The pharmacovigilance system is carried out by certain key activities which are depicted in the figure below:

The Pharmacovigilance system takes place through a safety database where the safety information of the product is collected, managed and analyzed by the pharmaceutical companies for monitoring potential adverse events, signal detection and assessing the benefit risk ratio. Apart from pharmaceutical companies, regulatory authorities as well as other stakeholders utilize this database to monitor the safety and effectiveness of medical products throughout their lifecycle.

Pharmacovigilance Safety Databases

A wide range of safety related information is stored and managed including adverse events, medical history, laboratory data and other relevant information. The data that are pooled in the safety databases are from various sources like the post marketing surveillance, clinical trials conducted, spontaneous reporting and literature reviews. Safety reports can be generated from safety databases which are crucial when submitted to the regulatory authorities for product approval, labeling, risk management and other activities.

Pharmaceutical companies use various safety databases to monitor the safety and effectiveness of their medical products. Some of the databases include Argus Safety, ARISg, PV Works, etc. Some of the Global Safety database are:

VigiBase

It is the most abundant source of pharmacovigilance data in the world. It is developed and maintained by the Uppsala Monitoring Centre (UMC) situated in Uppsala, Sweden on behalf of WHO. The WHO Programme for International drug Monitoring (WHO PIDM) created in 1968 aims to collect evidence for harm to patients from as many sources as possible.

More than 150 members of the WHO PIDM submitted structured and detailed Individual Case Safety Report (ICSR) to VigiBase. Since 1978, the UMC has been responsible for the WHO PIDM’s operational aspect. It is the largest database with around 40 million suspected adverse effects and is updated continuously with incoming reports.

FAERS & VAERS

FDA’s Adverse Event Reporting System (FAERS) is the FDA’s database which contains adverse event reports, reports of medication error, complaints of product quality resulting in adverse events which were submitted to the FDA. The FAERS database’s information structure follows international safety reporting guidance issued by the ICH (E2B). The adverse events and medication errors are coded using MedDRA (Medical Dictionary for Regulatory Activities).

Vaccine Adverse event Reporting System (VAERS), a national vaccine safety surveillance program is run by the FDA and the Centre for Disease Control and Prevention (CDC). In VAERS, the data from the reports of adverse events caused due to vaccination are collected and analyzed. Since 1990, 2 million reports have been received.

EudraVigilance

It is the system for managing and analyzing information on suspected adverse reactions of medicines marketed or studied under the European Economic Area (EEA). On behalf of the European Union (EU) medicines regulatory network, the European Medicines Agency (EMA) operates the system. In December 2001, EMA launched the first operating version.

It facilitates the exchange of ICSRs electronically between EMA, NCA (National Competent Authority), MAH (Marketing Authorization Holders) and the sponsors of clinical trials in EEA. EudraVigilance supports the safe and effective use of medicines by possible safety signal’s early detection and evaluation. It also allows for better product information for EEA authorized medicines.

Compliance With Pharmacovigilance Regulations During Clinical Trials

Pharmacovigilance is a mandatory global activity. Even though each regulatory authority has different regulations for presenting the safety data gained through pharmacovigilance, the end goal is to promote the safe and effective use of medicines among the public. So, compliance with the regulation is also crucial to promote this goal.

During clinical trials, adverse events are very common and must be recorded and reported. There is a time limit for reporting serious adverse events, suspected adverse events, unexpected serious adverse events, etc. Proper system for data collection, storing and monitoring, analysing the data for any potential adverse events, detection of signal patterns, following GCP, GVP and other respective regulatory guidelines, developing risk assessment and management plans are some of the key aspects of pharmacovigilance compliance.

Being in compliance can lead to an assurance of the trial participant safety, safety and effectiveness of the investigational product, decrease in product recalls and rejection, public safety, safety data generation and faster regulatory approvals leading to expedited marketing.

Pharmacovigilance Audits In Clinical Trials

The Pharmacovigilance audits is a systematic, detailed, independent and documented process which reviews a company’s pharmacovigilance system to see if it is working effectively. It must verify, by examining and evaluating the objective evidence, how appropriate and effective the implementation and operation of the pharmacovigilance system is.

Audits are conducted to determine how well the audit criterias are fulfilled, contribution in improvising the risk management and processes control and governance. A risk-based approach towards audit will focus on the highest risk areas to the pharmacovigilance system of the organization along with the quality system for pharmacovigilance activities.

For strategic, tactical and operational planning of pharmacovigilance audit activity in the organization, proper documentation of risk assessment must be done.

The auditors' findings must be documented in an audit report. It must be communicated in a timely manner to the management. The audit process must have mechanisms to communicate the findings with the auditee and receive feedback, reporting to the management as well as other relevant parties. Based on the risk level, findings should be graded, showing the criticality in pharmacovigilance systems. The grading system must be described in the description of the quality system for PV.

t is the responsibility of the management of the organization to ensure a mechanism is there to effectively address the issues identified through the audits. Root cause analysis, impact analysis of the findings and preparation of corrective and preventive action, if applicable. To show that the issues arose during audits were addressed, evidence to completion of actions must be recorded.

Staying in compliance with the regulatory requirements is itself a major challenge. Running proper pharmacovigilance activities, preparing for pharmacovigilance audits and associated activities can be hectic. Moreover, it is easy to make mistakes and fail to miss crucial information. Artixio’s team of experts can guide you through each step efficiently. Connect with us through info@artixio.com

FAQs

Q. Why is pharmacovigilance important during clinical trials?

A. Pharmacovigilance is important to identify potential adverse events arising at the time of clinical trials; to understand the severity, frequency, rarity and/or commonality of the adverse effect, PV plays an important role. It ensures the safety of the subject participants which assures the safety of the consumers later on.

Q. What is adverse event reporting in clinical trials?

A. Adverse event reporting is the reporting of an adverse event that had happened to one or more study subjects participating in the clinical trial. The adverse event is an undesirable experience which is associated with the use of medical products.

Q. What are the challenges in pharmacovigilance for clinical trials?

A. Timely reporting of the adverse effects, difficulty in finding causal relationship between the event and the drug, underreporting, limitation of the sample size in a trial, complying with the complex regulatory requirements, short study duration and data overload are some of the challenges in PV for clinical trials.

Q. How do technology and AI support pharmacovigilance in clinical trials?

A. Electronic data capture, automatic detection, real time monitoring, AI algorithms optimization, analyze large databases for signal detection, effective and easy way for collecting, managing and analyzing data, time saving, etc. are some ways by which technology and AI support PV in trials.