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RGA6212 Fall 2022 Copyright 2022 © by Northeastern University Online 1 RGA 6212 Week 1: Introduction to Safety Science & Pharmacovigilance (Drugs, Biologics, & Medical Devices) Part 1 Instructor: Amanda McEwen.

[Audio] I hold a Bachelor's degree in Economics and Finance from Rutgers University, and a Master's degree in Health Care Administration from Northeastern University. Over the course of 10 years, I have worked in the field of health care, mainly with safety science, pharmacovigilance, and medical devices. Furthermore, I have developed and conducted safety training sessions at both the state and federal levels. My expertise in this domain has made me a beneficial resource for health care providers, regulatory agencies, and manufacturers..

[Audio] This course focuses on Safety Science and Pharmacovigilance. Participants will get an in-depth look into the pre-approval and post-approval safety monitoring fields. Furthermore, the Drug Development process, where Safety Science resides, will be studied. Additionally, Nonclinical Safety Guidance Documents such as the International Conference on Harmonization (ICH) will be examined. Basics of Nonclinical Safety will be covered. Clinical Safety Guidance like the FDA and EMA Safety related guidance documents will also be discussed. The course will give a basic understanding of Clinical Trials and key clinical safety-related concepts..

[Audio] The readings this week give a solid basis by introducing the terminology and key tenets of pharmacovigilance. Mr. Colbert's Chapter 1 is especially useful to talk about in class as it characterizes essential safety-related terms and makes apparent the contrast between pre-approval and post-approval terms and terms. We will chiefly use ICH E2A as the primary resource for safety-related definitions. It is also important to be conscious of the difficulties in interpreting safety terminology definitions in practice..

Readings Recap Bookmark this page  RGA6212 Fall 2022 Copyright 2022 © by Northeastern University Online 5.

[Audio] Safety Science is an essential concept in the lifecycle of drugs, biologics and medical devices. Through continuous data collection and analysis, it is possible to gain insight as to how these products affect our bodies, and prioritize patient safety. Both pre- and post-market data is collected and analyzed to identify and address any safety concerns..

[Audio] Pharmacovigilance is the practice of proactively and systemically monitoring the safety of pharmaceutical products from pre-approval through post-marketing stages, originating from the Greek words 'pharmakon' and 'vigilare', meaning drug and to keep watch, respectively. The scope of pharmacovigilance activities encompasses monitoring and assessing adverse drug reactions (ADRs) both before and after drug approval, including monitoring of ADRs during clinical trials and in the post-marketing setting to ensure the safety and efficacy of the pharmaceutical product..

[Audio] Safety Science plays an important role in pharmacovigilance, which is a vital part of the therapeutic lifecycle. It entails understanding the functioning of a drug, biologic, or medical device, such as its absorption, distribution, metabolism, and excretion in the body, and conducting statistical analysis of nonclinical and clinical safety data. It also includes devising nonclinical and clinical study designs, recognizing and defining pharmacovigilance events such as adverse events, and being aware of the regulatory safety reporting requirements. This knowledge allows for individual and collective safety data to be evaluated and reported to ensure the safe use of drugs, biologics, and medical devices..

[Audio] The intersection of safety science and pharmacovigilance must be considered throughout a product's development lifecycle. It is essential that safety-related considerations be taken into account during pre-approval and post-approval phases for drugs, biologics, and medical devices. These considerations must also be integrated into regulatory strategies and the risk-benefit assessments of products in order to ensure effective and safe outcomes for patients." At the intersection of safety science and pharmacovigilance lies the crucial importance of considering safety-related considerations throughout the development lifecycle of drugs, biologics, and medical devices. From pre-approval to post-approval stages, safety must be taken into account in order to create effective and safe outcomes for patients. Risk-benefit assessments and regulatory strategies should certainly be part of this process, ensuring that the ultimate product is safe for its users..

[Audio] Pharmacovigilance (PV) is an essential part of the medical industry, covering the production, distribution, and usage of medical products such as drugs, biologics, and medical devices. Put simply, Pharmacovigilance is the science of monitoring, assessing, and preventing medication-related side effects and risks. Pre-market PV and Regulatory Affairs (RA) activities involve the evaluation of safety and efficacy data, while post-market PV and RA activities centre on safety surveillance and risk management. Pharmacovigilance and Regulatory Affairs are intertwined, working together to ensure the highest level of safety for those in the medical field..

[Audio] Safety science and pharmacovigilance play an increasingly important role in modern health care. As health professionals, we must make sure that the public is informed of the latest developments and how they affect public health. We must strive to ensure that people have access to the best and safest treatments available and that they are knowledgeable about the safety of the medications they are using. Being transparent and providing up-to-date information is key to ensure public safety and security when making treatment decisions..

[Audio] When discussing patient safety in regards to drugs, biologics, and medical devices, some essential terms to keep in mind include side effects, adverse events, serious adverse events, pharmacovigilance, medication errors, overdoses, emergencies, hospitalization, contraindications, and death. Are there any other terms that should be considered?.

[Audio] Direct consumer advertising is a prominent marketing technique used in the US and New Zealand, employing creative and sometimes provocative initiatives to deliver a message to the public, such as the widely-known ad for the sleep medication Lunesta. However, with the growing understanding of the potency of pharmaceuticals, an important question arises: where do all these potential side effects originate?.

[Audio] Rigorous safety testing is required by the FDA before a drug can be approved, Inbrija included. To gain approval, the FDA collected years of safety data from clinical trials, which provides the safety information included in the package insert/label of the drug. Even after approval, manufacturers must still collect and report safety information to protect patients from any risks that may occur..

[Audio] Label information generated from nonclinical and clinical safety data is a core component of safety science and pharmacovigilance. It is essential to make sure all drugs, biologics and medical devices are accurately labeled with known risks and potential side-effects. Health care providers and patients should have access to the latest information on therapeutic products, so they are able to make informed decisions regarding their healthcare. Companies must ensure their labels completely reflect the latest scientific knowledge on the products, as regulated by the FDA in the United States..

[Audio] The FDA has a process in place to ensure that the most up-to-date safety information is available for medicines, drugs, and devices. This process requires manufacturers to submit periodic reports, referred to as "RGA6212 Fall 2022", at intervals of 6 to 12 months. These reports enable patients, physicians, and other medical industry professionals to stay informed about the changing safety landscape of the product. Post-approval safety updates are an essential part of pharmacovigilance and it is important to review and revise the approved product labeling..

[Audio] Drug safety information requires a comprehensive lifecycle approach that accounts for nonclinical and clinical information. Nonclinical toxicology and pharmacology studies are used to predict potential side effects in humans while the ICH Safety guidance (S) is used to provide guidance in this area. Clinical testing is conducted in a stepwise process (phase 1 to 3) to learn about in-human side effects of the drug. Pre-market pharmacovigilance is used to monitor clinical safety and compliance with ICH Efficacy guidance (E2A-E2F). After a drug has been approved for sale, drug label safety information maintenance and post-approval pharmacovigilance are used to learn about post-approval side effects and to maintain compliance with ICH Efficacy guidance (E2A-E2F) and other post-approval guidance documents from the FDA. RGA6212 Fall 2022 Copyright 2022 © by Northeastern University Online..

[Audio] The drug safety information lifecycle ensures data is collected and analyzed from pre-approval testing through post-market surveillance. This helps to inform healthcare professionals and the public about the risk benefits of medications. Risk assessment is an important part of the decision-making process for selecting and prescribing treatments. By collecting and analyzing evidence about drug safety, health professionals can make more informed decisions about how to maximize the benefits of medications and minimize potential risks for patients..

[Audio] The Benefit-Risk framework is a principle used to assess the performance of drugs, biologics, and medical devices in terms of the balance between potential benefits and risks. This framework is particularly important in the development and approval of medical products. The Council for International Organizations of Medical Sciences (CIOMS) is a non-governmental and non-profit organization founded in 1949 with the aim of promoting public health by providing guidance on health research, medical product development, and safety. CIOMS was the first to introduce the modern concept of benefit-risk in medical product development, and this will be discussed further in Week 10..

[Audio] Safety Science plays a vital role in the creation of drugs, devices, biologics, and vaccines by assessing their potential risks and benefits. Before these products are permitted to be used clinically, a full understanding of both their risks and benefits is necessary to ensure their use will not be detrimental to the public..

[Audio] ICH is an international organization established in 1990 by authorities from the United States, Japan and the European Union. It provides a platform for collaborating on the development of standards for the safety, efficacy and quality of medicines. ICH does not have the role of a regulatory body, but provides useful guidance documents for the industry. Additionally, the Council for International Organizations for Medical Sciences (CIOMS) has developed benefit risk concepts with the help of ICH which enables the assessment of the risks and benefits of a treatment..

[Audio] Safety Science and Pharmacovigilance play an integral role in ensuring the regulatory compliance of medical products, as safety is a fundamental factor in the development of effective therapeutic solutions. To ensure approval, effective safety regulations must be in place along with pre- and post-approval risk management strategies. Consequently, the relevance of Safety Science and Pharmacovigilance should not be underestimated..

[Audio] Regulatory project managers are responsible for gathering and reporting safety data in a timely manner. Case processors or PVG specialists assess safety data to ensure it is recorded and reported properly. Regulatory Affairs Department, in some cases, houses the whole pharmacovigilance function which ensures safety standards are met and public informed of any safety issues with drugs, biologics, and medical devices..

RGA6212 Fall 2022 Copyright 2022 © by Northeastern University Online 24.

[Audio] This slide aims to explore the various regulatory tools available for reporting and analyzing safety information in pre- and post-approval spaces, such as regulatory meetings, individual case safety reports, and aggregate reports. Additionally, it will cover post-approval safety signal detection and label management. It is fundamental to grasp how these tools are used to accurately assess safety data and abide by relevant laws and regulations..

[Audio] When assessing the pre-approval safety of a drug, biologic, or medical device, all data collected in pre-clinical and clinical trials must be considered. This data is used to determine if the drug, biologic, or medical device is safe for human use. The evaluation of potential risks, benefits, and side effects associated with the drug, biologic, or medical device is essential for ensuring its safety before it is marketed..

[Audio] It is essential to comprehend the drug development procedure, especially with regards to the utilization of safety science and pharmacovigilance. The path to drug endorsement generally includes pre-clinical, clinical, and post-marketing stages. Pre-clinical and clinical studies give information that is then used to outline a safety profile for the drug and make admonitions and safeguards as needs be. Post-marketing stages involve a continuous cycle of safety monitoring and assessment of the item. This is accomplished through exercises, for example, pharmacovigilance, which comprises of gathering, observing, inquiring about, assessing, and evaluating data from healthcare suppliers and patients to distinguish any potential results of the drug. The aftereffects of pharmacovigilance can be utilized to modify the safety profile of the drug, and the safety information can be a significant factor in the general appraisal of the drug. Finally, safety science assumes a fundamental job in the drug development cycle, and pharmacovigilance and its related exercises help to guarantee that a drug can be investigated safely and utilized securely and adequately..

[Audio] Safety monitoring is an integral part of the drug development process, beginning in preclinical or nonclinical development and continuing even after a drug is approved for market. Experiments are conducted to anticipate and predict potential safety issues caused by a drug or biologic's mechanism of action and other properties, and manufacturers are continuously updating safety information based on these results..

[Audio] Non-Clinical Research is the first step in the complex Drug Development Process that may take several years to bring a drug to market. It involves animal toxicity studies for assessing safety, as well as pharmacokinetic and pharmacodynamic tests to examine ADME (absorption, distribution, metabolism, and excretion). The Pre-Clinical phase, which forms part of Non-Clinical Research, is often misunderstood to only refer to non-human studies. However, many aspects of safety development for non-humans take place alongside later stages of drug development and require years to complete. Being aware of the significance of Non-Clinical Research is essential to comprehend the importance of safety science in the drug development procedure..

[Audio] ICH and FDA M3(R2) are two important components related to safety for drug and biologic development. Nonclinical Safety Guidance provides guidance regarding design, aims, and timing of nonclinical work, and has been accepted by FDA and most competent authorities. M3 (R2) guidance document is set to have an update in Fall 2022..

[Audio] This slide informs you that the presentation you are seeing is subject to a copyright held by Northeastern University Online. The material in this presentation will be used for the course M3(R2) which will be offered in the academic term RGA6212, Fall 2022..

[Audio] We will be discussing the Nonclinical Safety Data Collection as defined by ICH M3(R2). This guidance document provides information on the data needed to support the safety of a new drug or biologic. This includes data from phase 1 and 2 studies to help decide on safe doses for human trials. This data should help in predicting what could occur when exposed to the drug in humans and in identifying target organs. It should also aid in providing registration support for nonclinical safety to support drug/biologic approval, as well as in identifying possible long-term toxicities such as carcinogenicity, reproductive toxicity, and immunogenicity..

[Audio] ICH M3(R2) represents a guidance document issued by the International Conference on Harmonisation in order to provide pharmaceutical companies with regulatory and scientific expectations for nonclinical safety data generation. It discusses the potential need for nonclinical safety studies and the data necessary to demonstrate safety in the drug development process. This document serves as an important resource for both drug development and pre-approval regulatory review. " This slide is about ICH M3(R2), an important guidance document issued by the International Conference on Harmonisation. This document outlines the expectations for nonclinical safety data generation necessary to demonstrate safety in drug development and pre-approval regulatory review. It discusses the potential need for nonclinical safety studies, and offers a comprehensive overview of the data that is necessary for drug development and review process. This document is a key resource for pharmaceutical companies and is a valuable tool in helping to ensure both drug safety and effective regulatory compliance..

[Audio] Nonclinical safety of drugs and biologics is an important factor to consider before they are approved for use. The International Conference on Harmonisation (ICH) has issued a number of guidelines to assist in the testing process. The U S Food and Drug Administration (FDA) has adopted the ICH guidelines and published additional guidance. A list of FDA-adopted ICH guidance documents is included in this slide. Understanding these documents will ensure that drugs and biologics are properly studied prior to approval..

[Audio] The FDA Nonclinical Guidance documents provide an in-depth look at the safety aspects of biopharmaceuticals, drugs, and medical devices. This guidance includes topics such as pre-clinical study designs and endpoints, as well as post-approval safety surveillance and monitoring strategies. The guidance further outlines various definitions that need to be kept in mind throughout the drug development process.” In this slide, we will explore the key FDA Nonclinical Guidance documents for drugs, biologics, and medical devices. These documents are critical for any drug development program, as they provide information on how safety considerations should be taken into account for both pre- and post-approval stages. We will discuss the documents in detail and review the important definitions outlined in the guidance documents..

[Audio] The International Conference on Harmonization (ICH) S6 guideline is particularly applicable to the development of biologics and is accepted by the US Food and Drug Administration (FDA) and most other Competent Authority (CA) organizations. At Northeastern University Online, we make sure our students stay abreast of these essential regulatory guidelines. One such course that will provide a thorough run-through of the topic is RGA 6212, which will be available for Fall 2022 semester..

[Audio] Preclinical safety is a vital element of the drug development process. Good Laboratory Practice (GLP) guidelines and regulations, provided in CFR 21 Part 58, must be adhered to when conducting tests. Pharmacological studies for drug properties, as well as toxicity studies for potential toxicity must be done. Furthermore, toxicokinetic and pharmacokinetic studies to examine drug absorption, distribution, metabolism, and elimination to better understand pharmacological and toxicological properties should be carried out. Acute toxicity and repeat-dose toxicity studies to evaluate the drug's toxic effects are also essential. Genotoxicity, carcinogenicity, reproductive toxicity, immunotoxicity and other toxicology studies are used to gauge the drug's safety, with the objective of providing a safe first dose for humans. Preclinical safety is a necessary step in the drug development process and is important to guard the safety of drugs prior to their use in humans..

ADME: Basics.

ADME: Basics.

ADME: Basics.

[Audio] CVT-301 is a dry powder formulation being investigated as a potential treatment for Parkinson's Disease. It is a levodopa inhalation powder which is intended to provide relief for patients during OFF episodes when current oral medications are insufficient. This medication is administered with a proprietary delivery system and aspires to deliver quick and dependable relief from motor fluctuations..

[Audio] CVT-301, also known as Inbrija, is an inhaled product for the treatment of Parkinson's Disease. This particular product had some interesting PK properties when tested on rats, and here's a look at the single dose data. As we can see, the Cmax peaked at 0.2 hour and the AUC was relatively low. These results were obtained in the Fall of 2022 at Northeastern University Online..

[Audio] Nonclinical ADME studies are an essential component in the drug development process. CVT-301, also known as Inbrija, is a prime example. This medication is employed for the treatment of Parkinson's disease. Single-dose pharmacokinetics has been used to study the medication in rats, in order to comprehend more thoroughly how the drug is absorbed and scattered in the body. Such data is essential for drug safety and efficacy, and provides crucial insights into the drug development process..

[Audio] Inbrija, designated as CVT-301, is a single dose drug used to address temporary Parkinson's symptoms. A rat model of pharmacokinetics was used to evaluate the drug, and the findings indicated rapid absorption and clearance. This serves as an exemplar of how nonclinical ADME studies promote assessment of medication security and efficacy..

[Audio] Nonclinical studies of CVT-301, also known as Inbrija, were conducted to determine its absorption, distribution, metabolism and excretion. Results from a single-dose rat pharmacokinetic study for CVT-301 showed rapid absorption and a Tmax of around 2 hours. The drug is used to treat adults with Parkinson's disease experiencing OFF episodes or episodes of insufficient symptom relief..

[Audio] Nonclinical ADME studies are used to evaluate the absorption, distribution, metabolism, and excretion of a drug such as CVT-301 (also known as Inbrija) in test models. This particular drug was studied in rats after multiple/repeat dose administration to understand its pharmacokinetic properties. The investigation of nonclinical aspects of a drug is an essential component of safety sciences and pharmacovigilance..

[Audio] To begin a phase 1 clinical trial, safety of the participants must be ensured. Nonclinical safety studies such as safety pharmacology, toxicology and absorption, distribution, metabolism and excretion must be conducted to determine a NoObservedAdverse Effect Level or NOAEL. This NOAEL will decide the safe starting dose for the human trial. Additionally, an Investigator's Brochure should be created and discussed in week 2 of the course..

[Audio] At the session, we will examine the determination of secure initial doses in Phase 1 trials. The analysis will focus on the significance of correct pharmacokinetic and pharmacodynamic assessment of a drug, biologic, or medical device before clinical trials. Additionally, we will go over the several reviews and regulatory guidelines required for identifying a safe starting dose. Lastly, we will investigate the components and considerations for an effective risk management plan..

[Audio] When determining a safe starting dose in Phase 1 Trials, it is important to consider the risk and benefit assessment for the potential drug in question. The EMA's Guideline on Good Clinical Practice provides specific recommendations in order to prioritize safety. RGA 6212 Fall 2022 states that the starting dose of a new drug should not exceed the lowest dose that is expected to produce a therapeutic effect, with the emphasis being placed on safety..

[Audio] Without greetings and without beginning with Today, the text reads: "As we come to slide 50 out of 50, let’s take a look into the subject of determining dose levels for Phase 1 studies. As we know, the maximum recommended starting dose (MRSD) is based on the readings of Week 2. This is a very important step towards further research. In non-clinical settings, we are able to determine the No Observed Adverse Effects Limit (NOAEL). It involves giving the relevant animal species the highest dose to establish a link to evidence of toxicity. In addition, there is a more conservative algorithm for determining the safe starting dose for “high risk” compounds called minimum anticipated biological effect level (MABEL). And with that, I would like to thank you all for your kind attention and wish everyone a safe and healthy day..