Pharmacovigilance 2024/2025 PDF

Pharmacovigilance Department of Social and Clinical Pharmacy Faculty of Pharmacy in Hradec Králové, Charles University PharmDr. Zuzana Juhásová, Ph.D. Social Pharmacy 2024/2025 Pharmacovigilance lecture: content Pharmacovigilance: definition, activities, s...

Pharmacovigilance Department of Social and Clinical Pharmacy Faculty of Pharmacy in Hradec Králové, Charles University PharmDr. Zuzana Juhásová, Ph.D. Social Pharmacy 2024/2025 Pharmacovigilance lecture: content Pharmacovigilance: definition, activities, significance Historic milestones Adverse Drug Reaction (ADR): definition and classification Stakeholders in pharmacovigilance: marketing authorization holder (MAH) healthcare professionals regulatory authorities (EMA, FDA, SÚKL) patients and patient organizations global organizations (UMC) Signal Information sources Benefit-risk ratio Regulatory actions Legislation  Pharmacovigilance pharmakon = drug (Greek), vigilare = to monitor/keep an eye on (Latin) Oversight of medicinal products after their authorisation in order to ensure maximum safety and the best possible balance between the benefits and risks of the medicinal product Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse drug reactions, with the aim of improving care and increasing patient safety and contributing to the protection of public health. Pharmacovigilance activities: Monitoring the use of medicinal products in daily clinical practice in order to identify previously unrecognized adverse reactions or changes in the nature of adverse reactions Evaluation of the risk-benefit balance of medicinal products to decide what regulatory action, if necessary, is necessary to make the use of medicines safer Implementing regulatory measures to minimize risks and providing information to healthcare professionals and patients to enhance the safe and effective use of medicinal products.  Pharmacovigilace = monitoring the safety of medicinal products after maketing authorization Pre-authorization Post-authorization Planning of risk Reports of Signal prioritization Evidence minimization suspected adverse detection and assessment activities drug reaction validation Main pharmacovigilance activities start after Regulatory maketing authorization action of the medication. However, planning of pharmacovigilance Communication Measurement of activities is required of regulatory impacts of before approval actions regulatory actions  Why do we need pharmacovigilance? Pre-authorization Real world clinical trials heterogeneous population Regular monitoring obese, pregnant, frail Highly older patients, different selected comorbidities, different population medication adherence abuse, misuse, off-label use drug interactions, medication errors  Limitations of pre-authorization clinical trials Low external validity External validity = the possibility of generalizing study results to another population, in a different environment, and under different conditions Patients included in pre-authorization clinical trials: Specific inclusion criteria, limited and monitored concurrent medication use, monitored for early symptoms of adverse drug reactions that can be reversed with proper treatment → Missing information: Adverse reactions associated with a population not included in the pre-authorisation (pre-approval) clinical trials: children, frail older patients, pregnant women, polymorbid patients, patients with liver/renal failure Adverse reactions associated with medication errors, off-label use, drug abuse,...  Limitations of pre-authorization clinical trials Short duration Small sample size Missing information: rare and very rare ADR Missing information: ADR type C (chronic) ADR type D (delayed) the rule of 3 a sample size three times greater than the frequency of the ADR is needed to have a 95% chance of detecting the ADR  History of pharmacovigilance Tragic crises have been the main drivers of change Reactive → proactive pharmacovigilance Czechoslovakia was among the first countries engaged in the WHO Programme for International Drug Monitoring Source: WHO-UMC  Milestones in evolution of pharmacovigilance 1937 1848 1915 1949 1961 Elixir sulfanilamide chloroform arsfenamin with ethylene glycol solvent chloramphenicol thalidomide Lancet invited Report of the Requirement of 1. Textbook Following the thalidomide doctors to report UK Medical preclinical drug Register of drug- tragedy, national national deaths related to Research safety testing related blood reporting systems were anesthesia Committee dyscrysia gradually established 1964 1965 1968 1995 2001 2010 2012 Yellow Card in EU directive WHO EMA Eudra- Directive Good PV the UK 65/65 Programme for (European vigilance 2010/84/EU Practise International Medicines Drug Monitoring Agency) Rofecoxib (Vioxx scandal) → Greater emphasis on drug safety Rosiglitazone Antidiabetic drugs → emphasis on cardiovascular safety Concerns related to rosiglitazone ↑ LDL, ↑ weight gain led regulatory agencies to mandate the assessment of cardiovascular safety for new antidiabetic medications Primary endpoints in clinical trials of antidiabetic drugs → clinical outcomes (instead of surrogate endpoints)  Adverse drug reactions Current EU definition: Adverse reaction is defined as a response to a medicinal product which is noxious and unintended Adverse reactions may arise from use of the product within or outside the terms of the marketing authorisation or from occupational exposure Directive 2010/84/EU WHO definition: Adverse drug reaction (ADR) = a response to a drug that is noxious, unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or for the modification of a physiological function. Types of ADRs that are mandatory to report Serious = an adverse reaction that: ❑ results in death ❑ is life-threatening ❑ requires hospitalization ❑ prolongation of existing hospitalization ❑ results in persistent or significant disability or incapacity ❑ is a birth defect Unexpected = the nature, severity or consequences of ADR are not consistent with the information laid down in the Summary of the product characteristics (SmPC)  Types of adverse drug reactions A Augmented dose dependent, predictable anticoagulants → bleeding peniciline → anaphylaxis B Bizzare hypersensitivity reactions suxametonium → malignant hyperthermia cumulative corticosteroids → Cushing's syndrome C Chronic (depend on the duration of treatment) amiodarone → pulmonary fibrosis teratogens: thalidomide, warfarin, lithium, teratogenesis, mutagenesis, D Delayed carcinogenesis valproate, phenytoin, isotretinoin antipsychotics → tardive dyskinesia rebound phenomen, withdrawal abrupt withdrawal of beta-blockers or E End of use syndrome clonidine → reflex tachycardia Failure of lack of effectiveness paroxetine (CYP2D6 inhibitor) + tamofixen F therapy (eg. due to drug-interactions) st. John's wort + oral contraceptives I ? Immediate rapid titration ACEi – orthostatic hypotension  Classification of ADRs by frequency classification used in the SmPC Examples: Very ≥ 1/10 patients tramadol – dizziness, nausea common tramadol – fatigue, vomiting, constipation Common 1/100 to 1/10 patients diclofenac – nausea, dyspepsia, rash tramadol – diarrhea Uncommon 1/1000 to 1/100 patients diclofenac – myocardial infarction tramadol – epileptiform convulsions Rare 1/10 00 to 1/1000 patients diclofenac – hypersensitivity tramadol – hallucinations, depersonalization Very rare < 1/10 000 patients diclofenac – liver necrosis, acute renal failure  Classification according to the organ system class Examples of ADR that led to withdrawal of MedDRA classification medications from the market or warnings: (Medical Dictionary for Drug Regulatory Affairs) Hematologic toxicity: chloramphenicol, felbamate, → classification used in the SmPC clozapine, ticlopidine, metamizole, sulfasalazine, rituximab, calcium dobesilate, trimethoprim-sulfamethoxazole, Blood and lymphatic system methimazole, carbimazole, propylthiouracil disorders Hepatotoxicity: tolcapone, troglitazone, trovafloxacin, Cardiac disorders ibufenac, bromfenac, benoxaprofen, lumiracoxib, Endocrine disorders nimesulide, propylthiouracil Gastrointestinal disorders Cardiotoxicity: rosiglitazone, rofecoxib, etoricoxib, Hepatobiliary disorders pergolide, phentermine, sibutramine Metabolism and nutrition disorders Torsade de pointes: astemizole, terfenadine, cisapride, Nervous system disorders clobutinol, mibefradil, sparfloxacin, grepafloxacin Psychiatric disorders Nephrotoxicity: phenacetin Renal and urinary disorders... Rhabdomyolysis: cerivastatin Stakeholders in pharmacovigilance Health Care Providers (HCP) Marketing Authorisation CRO (contract research Holder organization) Marketing Authorisation Holder outsourcing of (MAH) pharmacovigilance activities Regulatory authorities Health Care National SÚKL, EMA, FDA, MHRA,... Providers Regulatory Regulatory Authority authorities in Patients Patients (SÚKL) other countries & patient organizations Global organisations PRAC UMC UMC: worldwide signal detection (Uppsala European Medicines CIOMS, ICH: harmonization Monitoring Centre) Agency (EMA) ICSR database: Vigibase ICSR database: EudraVigilance  Health Care Providers A physician, pharmacist or other healthcare professional who has noticed a suspected serious or unexpected adverse reaction is obliged to: notify the organization responsible for pharmacovigilance provide assistance in the verification of data related to a suspected adverse reaction and, upon request, to make available the relevant documentation + keep up with the new information CAV E ! Dear healthcare professional ADRs letter  Patients and patient organisations Patients have a key role in building a better system of pharmacovigilance Patients are given the opportunity to report directly to the health authorities Patients are the ultimate beneficiaries of medicines and, therefore, their views should be heard → PV incorporates patients’ values and preferences into the scientific review process which could influence benefit risk decision making Representatives of patient organisations in the PRAC Decision Patient engagement and empowerment Patient-centered making pharmacovigilance raise awareness about reporting systems advocate for medication safety funding, policies, legislation Direct patient reporting involved in public awareness campaings transparency  Marketing Authorisation Holder Marketing Authorisation Holder (MAH) = the pharmaceutical company or other legal entity that has the authorisation to market a medicinal product MAHs must comply with pharmacovigilance regulations and collaborate with regulatory agencies in addressing safety concerns MAHs are responsible for collecting, reviewing and analysing information on suspected adverse reactions. They have to report this information to regulatory authorities on a periodic basis via Periodic Safety Update Reports Periodic safety update reports (PSURs) = comprehensive and critical analysis of the risk-benefit balance of the product, taking into account new or emerging safety information in the context of cumulative information on risk and benefits The MAH ensures update of safety information, such as changes in SmPC  Regulatory autorities EU European Medicines Agency (EMA) Modern regulation of medicines began in the 1960s in the wake of the occurrence of several thousand cases of phocomelia, a congenital limb abnormality, which was caused by exposure USA U.S. Food and Drug Administration to thalidomide during pregnancy In response to this tragedy, spontaneous adverse reaction reporting schemes were developed with the aim of providing signals of UK Medicines and Healthcare products Regulatory Agency (MHRA) unexpected hazards. Legislation was passed to provide regulatory Czech Republic controls on quality, safety, and efficacy of medicines through systems of standards for development, manufacturing, authorization, pharmacovigilance, and inspection. Regulatory autorities: roles in pharmacovigilance ❑ Long-term monitoring of safety in clinical practice to identify previously unrecognized signals of ADR ❑ Assessment of the risks and benefits of authorized medicines to take action to improve safety ❑ Provision of information to users to optimize safe and effective use of their medicines ❑ Monitoring the impact of any regulatoy action taken  PRAC = Pharmacovigilance Risk European Medicines Agency Assessment Committee PRAC →pharmacovigilance  European Medicines Agency PRAC = Pharmacovigilance Risk Assessment Committee EMA's committee responsible for assessing all aspects of risk management of human medicines the detection, prioritisation, assessment, recommendation and communication of the risks CHMP = Committee for Medicinal Products for Human Use CHMP considers the recommendations of the EMA's Pharmacovigilance Risk Assessment Committee on the safety of medicines on the market and when necessary, recommends to the European Commission changes to a medicine's marketing authorisation, or its suspension or withdrawal from the market.  Global organizations Uppsala Monitoring Centre (UMC) = WHO Collaborating Centre for International Drug Monitoring UMC advances the science and practice of pharmacovigilance, which covers the detection, assessment, understanding and prevention of adverse drug reactions and other medicine-related problems. management of VigiBase (global ICSR database) CIOMS Council for International Organizations of Medical Sciences harmonization ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Stakeholders in PV and their roles Healthcare Healthcare Regulatory autority professional Patient professional Marketing-authorization Marketing- holders are expected authorization holders to take action according submit Periodic to the recommendations Safety Update of regulatory autorities Reports (PSURs) to Marketing Authorisation Holder regulatory autorities  Signal Signal = information that arises from one or multiple sources, which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action New risk Newly detected signals serve as a trigger for further in-depth New aspect of known risk investigations - increased frequency - increased severity Usually more than a single report is required to generate a signal, depending - new at risk population upon the seriousness of the event and the quality of the information. Signal detection → Validation → Assessment Assessment of regulatory action withdrawal intended effects or risk unintended effects minimisation (since 2017) + prioritization measures Inputs Processes Outputs Spontaneous reports Signal identification Decision communication Epidemiological studies Signal evaluation Revised Summary of Product Clinical trials Risk-benefit review Characteristics (SmPC) and Patient Case reports published Expert advice Information Leaflet (PIL) in the literature Decision making Safety announcement Withdrawal from the market  Sources of information Signals can be detected from multiple different sources: Spontaneous reports of suspected adverse drug reactions Real-world evidence (pharmacoepidemiological studies) Drug utilization Published medical literature Pharmaceutical company data Non-clinical data (animal toxicology studies) Clinical Trials  Spontaneous reporting Spontaneous reporting is an unsolicited reporting of suspected adverse drug reactions by health care professionals or patients Individual Case Safety Report (ICSR) = a document in a specific format for the reporting of one or several suspected adverse reactions to a medicinal product that occur in a single patient at a specific point of time National regulatory authorities maintain reporting system e.g.: in UK – MHRA Yellow Card Scheme ADRs identified via spontaneous reporting: PPI – hypomagnesemia, statins – hyperglycemia, (es)citalopram – QT prolonagtion, antipsychotics – venous tromboembolic events, antiepileptics – adverse effects on bone, varenicline – depression, suicidal thoughts, St John´s wort – drug interactions, Aristolochia – renal failure, linezolide – optic neuropathy, bupropion- seizures Individual Case Safety Report databases Information about cases from all reports is entered into the ICSR database of State Institute for Drug Control EU (EAA) WHO USA under a unique identification number. EMA UMC US FDA All reports are transmitted to the European Union‘s Eudra FAERS ICSR database (EudraVigilance) and World Health Vigilance VigiBase VAERS Organization‘s (Vigibase) ICSR databases. Spontaneous reporting Advantages Disadvantages the entire population under-reporting 95 % of ADRs are not reported all medications only events suspected of ADR suitable to detect rare unsuitable to detect ADRs type C ADRs and very rare ADRs (chronic) and ADRs type D (delayed) continuous method reporting bias relatively inexpensive unknown denomination Hazell L, Shakir SA. Under-reporting of adverse drug reactions : a systematic review. Drug Saf. 2006;29(5):385-396.  Benefit-risk assessment The decision to approve a drug is based on its having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. This decision is based on the information available at the time of approval. The knowledge related to the safety profile of the product can change over time through expanded use in terms of patient characteristics and the number of patients exposed. Once a product is marketed, new information will be generated, which can have an impact on the benefits or risks of the product; evaluation of benefit-risk ratio should be a continuing process, in consultation with regulatory authorities Pharmacoepidemiology is essential for Pharmacoepidemiology assessing benefit-risk ratio of medications is discussed within by analyzing real-world data on their safety Pharmaceutical care I. and effectiveness  Regulatory actions Withdrawal from the market suspending/revoking marketing authorisations if the risks outweigh the benefits Risk minimization measures The benefit-risk ratio of a medicinal product can be improved by reducing the burden of adverse drug reactions through effective risk minimiaztion measures Regulatory actions minimize the risks  Risk minimisation measures Risk Minimisation measures (RMM) are interventions intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient should adverse reactions occur. The risk-benefit balance of a medicinal product can be improved by reducing the burden of adverse reactions or by optimising benefits, both through patient selection and treatment management (e.g.specific dosing regimen, relevant testing, patient follow-up). RMM should therefore support the optimal use of a medicinal product in clinical practice with the principal goal of providing the right medicine at the right dose and at the right time to the right patient and with the right information and monitoring. Right information Right monitoring  Risk minimisation measures ❑ Update of SmPC & PIL (Patient Information Leaflet) ▪ new ADR (warfarin – calciphylaxis) ▪ new warning (agomelatin – liver fuction monitoring) ▪ new drug-drug interaction (tamoxifen and CYP2D6 inhibitors) ▪ new contraindication (codein – children, diclofenac – cardiovascular disease) ❑ Legal status of a medicine (OTC to Rx only: dextromethorphan, ketoprofen) ❑ Control of package size (eg: maximum of 30 days supply) ❑ Pregnancy Prevention programme (e.g. valproate, retinoids, thalidomide) ❑ Educational materials (e.g. guides, checklist) ❑ Direct Healthcare Professional Communications  Legislation Legislation in the EU Legislation in the Czech Republic Directive 2010/84/EU Act No 378/2007 Coll. Act on Regulation (EU) No 1235/2010 Pharmaceuticals Further amendments: Regulation (EU) No 1027/2012 + Decree No 228/2008 Coll., on the marketing Directive 2012/26/EU authorisation of medicinal products Practical measures to facilitate the performance of pharmacovigilance in accordance with the legislation are available in the guideline on Good pharmacoVigilance Practices (GVP) GVP apply to marketing-authorisation holders, the European Medicines Agency and medicines regulatory authorities in EU Member States.  Pharmacovigilance Pharmacovigilance = science and activities relating to the detection, assessment, understanding and prevention of adverse drug reactions or any other drug-related problem Adverse drug reaction (ADR): a response to a medicinal product which is noxious and unintended serious ADR: results in death, life-threatening, requires hospitalization or the prolongation of hospitalization, results in disability or birth defect unexpected ADR: the nature or severity is not consistent with the SmPC Signal = information which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events that is judged to be of sufficient likelihood to justify verificatory action  Pharmacovigilance: significance Limitations of pre-authorization clinical trials: small sample size short duration low external validity Full safety profile includes adverse drug reactions (ADRs) which are: Rare and very rare ADRs (clinical trials are under-powered to detect rare ADRs) ADRs type C (chronic): cummulative – e.g.: rofecoxib and cardiovascular risk ADRs type D (delayed): teratogenic, carcinogenic – e.g.: thalidomide, diethylstilbestrol ADRs associated with populations not yet studied in clinical trials, for which different safety profile is suspected (children, frail older patients, pregnant women, several comorbidities) ADRs due to medication errors (e.g. methotrexate), associated with abuse (e.g. flunitrazepam)  Spontaneous reporting Spontaneous reporting is an unsolicited reporting of suspected adverse drug reactions by health care professionals, patients, and other individuals. limitations: under-reporing, unknown denominator, reporting bias Individual Case Safety Report (ICSR) = document in a specific format for the reporting of one or several suspected adverse reactions to a medicinal product that occur in a single patient at a specific point of time ICSR databases EU: EudraVigilance (maintained by European Medicines Agency) WHO: VigiBase (maintained by Uppsala Monitoring Centre) Stakeholders in Pharmacovigilance Patients Healthcare providers – report suspected ADR that are serious and unexpected Marketing Authorisation Holders (MAH) monitor the safety of their medicinal products Regulatory autorities (SÚKL, EMA, FDA, MHRA) maintain ICSR databases: Eudravigilance (EMA), FAERS (U.S. FDA) guidelines, inspections, benefit-risk assessment, regulatory actions, communication Global organization: Uppsala Monitoring Centre (UMC) UMC = designated WHO Collaborating Centre for International Drug Monitoring global ICSR database: Vigibase → signal detection  Regulatory actions in pharmacovigilance EMA: Pharmacovigilance Risk Assessment Committee (PRAC) → PRAC recommendations: Examples: cisapride, tetrazepam, benoxaprofen, troglitazone, rosiglitazone, cerivastatin, sibutramine, ❑ Withdrawal from the market rimonabant, phentermin, rofecoxib, valdecoxib, terfenadine, astemizole, mibefradil, grepafloxacin, when risks > benefits diethylstilbestrol ❑ Risk minimization measures SmPC and PIL update : new ADR, new contraindication, change of indication or dosing change of package size change of legal status (OTC to prescription only) pregnancy prevention programme communication Abbreviations ADR (Adverse drug reaction) MHRA (Medicines and Healthcare products CRO (Contract research organization) Regulatory Agency) = drug regulatory agency in UK CHMP (Committee for Medicinal Products for Human Use) PRAC (Pharmacovigilance Risk Assessment Committee) EMA (European Medicines Agency) RMM (Risk Minimisation measures) FAERS (FDA Adverse Event Reporting System) RWD (Real Word Data) GVP (Good Pharmacovigilance Practices) RWE (Real Word Evidence) ICSR (Individual Case Safety Report) UMC (Uppsala Monitoring Centre) MAH (Marketing Authorisation Holder) U.S. FDA (Food and Drug Administration) MedDRA (Medical Dictionary for Drug Regulatory Affairs) VAERS (Vaccine adverse event reporting system) Literature and other sources Andrews EB & Moore N. Mann’s pharmacovigilance. 3rd ed. Chichester, West Sussex: John Wiley & Sons Inc; 2014. ISBN: 978-0-470-67104-7 Bate A. Evidence-Based Pharmacovigilance: Clinical and Quantitative Aspects. New York: Humana Press; 2018. ISBN: 978-1-4939-8816-7 Dixon T. Clinical Pharmacy Education, Practice and Research: Clinical Pharmacy, Drug Information, Pharmacovigilance, Pharmacoeconomics and Clinical research. Amsterdam: Elsevier. 2019. ISBN: 978-0-12-814276-9 Reminder: Report PFS Symptoms to National Pharmacovigilance Authorities - The Post-Finasteride Syndrome Foundation Edwards IR & Lindquist M. Pharmacovigilance critique and Ways Forward. Cham: Springer International Publishing; 2017. ISBN 978-3-319-40399-1 WHO-UMC e-learning: https://learning.who-umc.org/ EMA = European Medicines Agency ISOP = International Society of Pharmacovigilance Copyright and fair use This lecture reproduced copyrighted material. 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