GVP, Surveillance and Recalls 2022 PDF

Pharmacovigilance (PV), Post Market Surveillance and Product Recalls Dr Joseph O’Shea ✉ [email protected] ☎ 1665 Adverse Drug Reactions (ADR) “Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy” It is estimated that:...

Pharmacovigilance (PV), Post Market Surveillance and Product Recalls Dr Joseph O’Shea ✉ [email protected] ☎ 1665 Adverse Drug Reactions (ADR) “Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy” It is estimated that: ~ 5 % of all hospital admissions are caused by ADRs ~ 5 % of hospitalized patients will experience an ADR during their hospital stay, ADRs cause 197,000 deaths annually throughout the EU Many ADR’s can only be detected after a medicine has been authorised i.e full safety profile of medicines can only be known once they have entered the market. Historically, the main source of information on the occurrence of ADRs has been spontaneous reporting by healthcare professionals. These estimates formed the foundation of a major reform of the European regulatory system for pharmacovigilance, Implemented in July 2012. WHO Pharmacovigilance (PV) Such ADR instances led drug regulatory authorities world wide to develop much more sophisticated approaches to the preclinical testing and clinical evaluation of drugs before marketing and to an increased awareness of adverse effect of drugs and methods of detecting them Pharmacovigilance https://youtu.be/dE6o1xsZhVU Timeline of events in pharmacovigilance McBride’s Letter Pharmacovigilance (PV) Prior to a medicine being marketed, evidence of its safety and efficacy is limited to results from clinical trails. Post authorisation the medicine is used in a large number of patients, for extended periods of time and often in combination with other medicines  side effects It is essential that the safety of all medicines is monitored throughout their use in healthcare practice Pharmacovigilance (PV) is the study of the safety of marketed drugs under the practical conditions of clinical use in the community In Ireland, the HPRA is responsible for monitoring medicine safety, including operation of the national adverse reaction reporting system. http://www.ema.europa. Pharmacovigilance (PV) Pharmacovigilance has been defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine- related problem. In line with this general definition, underlying objectives of the applicable EU legislation for pharmacovigilance are: preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure; promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public. Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public health. http://www.who.int http://www.hpra.ie Pharmacovigilance (PV) PV comprises collecting and managing data on the safety of medicines, evaluating this data and deciding to act to protect public health. This system ensures that any product, which presents an unacceptable level of risk, can be rapidly withdrawn from the market (RECALLS - LATER). PV heavily focuses on ADRs Pharmacovigilance is vital for the advancement of medical understanding, contributing to the safety profiles of existing drugs, future research, drug development and epidemiological studies. Ultimately leads to improvements in patient care Directive 2010/84/EU Major change in European Pharmacovigilance was observed with the new legislation (Directive 2010/84/EU), in 2012 Main changes in the new legislation were: Modification of the definition of adverse drug reactions (ADR); Greater involvement of patients and citizens in Pharmacovigilance activities; Strengthening of the Eudravigilance database containing reports of suspected reactions reported by all EU Member States; Increasing transparency and timeliness of important information on Pharmacovigilance problems; Obligation of “additional monitoring” for the products contained in the specific list kept by the EMA; Possibility to impose further safety and/or efficacy studies on the certificates of marketing authorization at the time of granting the trust; Establishment within the EMA of the Pharmacovigilance Risk Assessment Committee (PRAC). Good pharmacovigilance practices (GVP) A set of measures drawn up to facilitate http://www.ema.europa.eu/ema/ind the performance of PV in the EU. ex.jsp?curl=pages/regulation/docum GVP apply to ent_listing/document_listing_00034 (i) marketing-authorisation holders 5.jsp&mid=WC0b01ac05804fcdb1 (ii) the European Medicines Agency (EMA) and (iii) medicines regulatory authorities in EU Member States (HPRA in IRL). They cover medicines authorised centrally via the Agency as well as medicines authorised at national level. Pharmacovigilance in the product lifecycle Research and development Marketing authorisation Post-authorisation EudraVigilance Risk management European Risk Management Strategy (ERMS) Good pharmacovigilance practices (GVP) Incident management plan Medical literature monitoring Medication errors Medicines under additional monitoring Periodic safety update reports Pharmacovigilance systems Post-authorisation safety studies Regulatory and procedural guidance Signal management Good pharmacovigilance practices (GVP) Set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU). GVP apply to marketing-authorisation holders European Medicines Agency (EMA) medicines regulatory authorities in EU Member States Guideline on GVP was a key deliverable of the 2010 pharmacovigilance legislation. The guideline on GVP is divided into chapters that fall into two categories: modules covering major pharmacovigilance processes; product- or population-specific considerations vaccines, biological medicinal products and the paediatric population published Geriatric population guidance TBF https://www.ema.europa.eu/en/human-regulatory/post- authorisation/pharmacovigilance/good-pharmacovigilance-practices Guideline on good pharmacovigilance practices (GVP) Pharmacovigilance system is a system used by organisation to fulfil the tasks and responsibilities designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. MAH, EMA, NCA Overall quality objectives of a pharmacovigilance system are: complying with the legal requirements for pharmacovigilance tasks and responsibilities; preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure; promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and thepublic; and contributing to the protection of patients’ and public health. Principles of GVP Specific systems required for Continuous monitoring of pharmacovigilance data Scientific evaluation of all information on the risks of medicinal products as regards patients’ or public health Submission of accurate and verifiable data on serious and non-serious adverse reactions Quality, integrity and completeness of the information submitted on the risks of medicinal products Effective communication by the marketing authorisation holder with competent authorities, including communication on new or changed risks Update of product information by the marketing authorisation holder in the light of scientific knowledge Appropriate communication of relevant safety information to healthcare professionals and patients Specific procedures required for Submission of adverse reaction data to EudraVigilance within the legal timelines Retention of pharmacovigilance data and documents relating to individual authorised medicinal products Product information is kept up-to-date by the marketing authorisation holder in the light of scientific knowledge Critical pharmacovigilance processes Critical Processes Continuous safety profile monitoring and benefit-risk evaluation of authorised medicinal products Establishing, assessing and implementing risk management systems and evaluating the effectiveness of risk minimisation Collection, processing, management, quality control, follow-up for missing information, coding, classification, duplicate detection, evaluation and timely electronic transmission of individual case safety reports (ICSRs) from any source Signal management Scheduling, preparation submission and assessment of periodic safety update reports Meeting commitments and responding to competent authorities - provision of correct and complete information Interaction between the pharmacovigilance and product quality defect systems Communication about safety concerns between marketing authorisation holders and competent authorities Communicating information to patients and healthcare professionals about changes to the risk-benefit balance of products Keeping product information up-to-date with the current scientific knowledge implementation of variations to marketing authorisations for safety reasons according to the urgency required Process monitoring Reviews of the systems by those responsible for management Audits compliance monitoring Inspection evaluating the effectiveness of actions taken with medicinal products for the purpose of minimising risks and supporting their safe and effective use in patients Overview of pharmacovigilance Post Marketing Clinical trials Detect Signal Surveillance Estimate incidence Risk Benefit is No Yes Is there a Risk based Estimate severity unchanged – no causal action required relationship review Inform No Is risk Yes benefit Change ratio Act Label changed Restrict Use/ Withdrawal QPPV MAH shall have permanently and continuously at its disposal an appropriately qualified person responsible for pharmacovigilance in the EU (QPPV) Submit the name and contact details of the QPPV to the competent authorities Personally responsible for implementation of PV system – medically trained Sufficient authority to influence the performance pharmacovigilance activities MAH should ensure that mechanisms are in place so that the QPPV receives all relevant information related to Emerging safety concerns and any other information relating to the benefit-risk evaluation of the medicinal products covered by the pharmacovigilance system Ongoing or completed clinical trials and other studies the marketing authorisation holder is aware of and which may be relevant to the safety of the medicinal products Information from sources other than from the specific marketing authorisation holder, e.g. from those with whom the marketing authorisation holder has contractual arrangements Procedures relevant to pharmacovigilance which the marketing authorisation holder has in place at every level in order to ensure consistency and compliance across the organisation. Role of QPPV Responsibilities of QPPV having an overview of medicinal product safety profiles and any emerging safety concerns; having awareness of any conditions or obligations as part of the marketing authorisations having awareness of risk minimisation measures; review and sign-off of protocols of post-authorisation safety studies conducted in the EU having awareness of post-authorisation safety studies requested by a competent authority ensuring conduct of pharmacovigilance and submission of all pharmacovigilance-related documents ensuring necessary quality, the correctness and completeness, of pharmacovigilance data providing any other information relevant to the benefit-risk evaluation to the competent authorities in Members States and the Agency; providing input into the preparation of regulatory action in response to emerging safety concerns (e.g. variations, urgent safety restrictions, and communication to patients and healthcare professionals); acting as a single pharmacovigilance contact point for the competent authorities in Member States and the Agency on a 24-hour basis and also as a contact point for pharmacovigilance inspections. Signal Detection A safety signal is information on a new or known adverse event that may be caused by a medicine and requires further investigation EMA, NCAs and MAH are responsible for detecting and managing safety signals. Can be detected from a wide range of sources Spontaneous reports Clinical studies Scientific literature EudraVigilance database is an important source of information on suspected adverse reactions and signals Presence of a safety signal does not directly mean that a medicine has caused the reported adverse event. Assessment of safety signals establishes whether or not there is a causal relationship between the medicine and the reported adverse event. Evaluation of safety signals is part of routine pharmacovigilance and is essential to ensuring that regulatory authorities have the most up-to-date information on a medicine's benefits and risks. Signal detection: Pre-marketing: Clinical Trials Main method to gather information in pre-marketing phase Rigorous determination of cause-effect relationship between treatment and outcome Protocol should be rigorously designed to detect ADRs Initial determination of risk/benefit ratio Information submitted as part of CTD Pivotal studies Limitations Limited number of patients Will not identify rare ADRs Shorter duration ADRs with long latency Specific populations May not be fully representative of population as a whole Post-marketing surveillance aims to overcome shortcomings Post Authorisation/Market Surveillance Clinical trials are carefully planned and carried out on a limited number of patients When a drug is first marketed, much may be known about its efficacy while relatively less may be known about its safety profile (e.g. long term effects, drug interactions etc) Therefore post-marketing surveillance is essential to help identification of drug safety problems not detected during pre-marketing evaluation (essentially Phase IV). Ensures the safety and efficacy of post marketed medicine on the market Identifying and Reporting ADRs Detection and Identification of ADRs result from Reporting of suspected adverse reactions new clinical trial data literature reports Once a signal (e.g. ADR) is identified, further evaluation and additional data are necessary to help determine its significance This includes gathering information between exposed and unexposed patients (to confirm or refute the signal) identify potential risk factors estimate the incidence http://www.hpra.ie Identifying and Reporting ADRs Healthcare professionals (including doctors, dentists, pharmacists and nurses) are requested to report suspected adverse reactions observed in their practice. Of particular importance are all suspected reactions to newly authorised products serious reactions to established products, products undergoing additional monitoring and suspected reactions to vaccines or medicines used in pregnancy MAHs required to ensure that an appropriate system for pharmacovigilance is in place Assume responsibility for marketed medicines Ensure appropriate action may be taken when necessary MAHs should ensure PV systems are in line with their regulatory obligations Regularly monitored to ensure compliance. Pharmacovigilance inspections conducted by HPRA on a routine/triggered basis Expedited reporting requirements HPRA ADR Reporting http://www.hpra.ie/homepage/medicines/safety-information/reporting-suspected-side-effects Yellow Card Medicines and Healthcare products Regulatory Agency (MHRA) is the UK manage the Yellow Card Scheme UK system for collecting and monitoring information on suspected safety concerns or incidents involving medicines and medical devices Relies on voluntary reporting of suspected ADRs by health professionals and patients. Provides an early warning that the safety of a product may require further investigation The Scheme collects information on suspected problems or incidents involving 1. side effects (also known as adverse drug reactions or ADRs) 2. medical device adverse incidents 3. defective medicines (those that are not of an acceptable quality) 4. counterfeit or fake medicines or medical devices 5. safety concerns for e-cigarettes or their refill containers (e-liquids) Yellow Card EudraVigilance European Union Drug Regulating Authorities Pharmacovigilance) A centralised European database of suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the European Economic Area (EEA). A single repository for reports of suspected adverse reactions seen in healthcare practice and clinical trials. It is used by Member states, the Agency and industry. The PRAC** evaluates safety signals from EudraVigilance and may recommend regulatory action as a result EudraVigilance supports safe and effective use of medicines by facilitating – The electronic exchanges of individual case safety reports between EMA, national competent authorities, marketing authorisation holders and sponsors of clinical trails in the EEA Early detections and evaluation of possible safety signals Better product information for medicine authorised in the EEA **Pharmacovigilance Risk Assessment Committee (PRAC) The committee that is responsible for assessing all aspects of the risk management of medicines for human use. Risk Management Medicines are authorised on the basis that its benefits outweigh its risks for the target population All potential or actual adverse reactions are identified by the time an initial marketing authorisation is granted Aim of risk management is to address uncertainties in the safety profile at different points in the lifecycle, and to plan accordingly. Marketing authorisation applicants are required to submit risk management plans, which include information on Medicine's safety profile Plans for pharmacovigilance activities designed to gain greater knowledge How risks will be minimised in patients and how those efforts will be measured. Companies must submit a risk management plan (RMP) at the time of application for a marketing authorisation All RMPs must include a summary, which distils the technical detail of the document into a public-friendly format. For centrally authorised medicines, the Agency publishes this summary alongside the European public assessment report. RMPs are continually modified and updated throughout the lifetime of the medicine as new information becomes available. Companies need to submit an updated RMP: at the request of EMA or an NCA; whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as a result of an important pharmacovigilance or risk-minimisation milestone being reached. https://www.ema.europa.eu/en/documents/rmp-summary/thymanax-epar-risk-management-plan-summary_en.pdf Risk Management Plan - Contents Amount of information should be proportionate to the identified risk and the potential risk, and will depend on the type of medicinal product, its risks, and position in the lifecycle Post Authorisation Surveillance (PASS) A post authorisation safety study (PASS) is any study relating to an authorised medicine, carried out with the intention of identifying and quantifying a safety concern, confirming the safety profile of a medicine or measuring the effectiveness of risk minimisation measures. A PASS may be carried out to (i) provide reassurance about the absence of a safety concern related to a specific adverse reaction, (ii) further investigate known safety concerns or (iii) to study the use of the medicine in patients who were not included in clinical trials e.g. older patients or pregnant women. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/doc ument_listing_000377.jsp&mid=WC0b01ac058066e979 http://www.hpra.ie Post Authorisation Surveillance (PASS) A PASS may be conducted voluntarily by a drug company or it may be imposed by a regulatory authority if there are safety concerns with the use of the medicine Condition to MA - key to the risk-benefit profile (category 1 studies) Specific obligations in the context of a conditional MA (category 2 studies) investigate a safety concern or evaluate the effectiveness of risk minimisation activities (category 3 studies) PASS studies are closely supervised by regulatory authorities in coordination with the European Medicines Agency (EMA) Study protocols, progress reports and final study results are submitted to the EMA and regulatory authorities for review. Agency publishes the protocols, abstracts and final study reports of PASSs in the EU post-authorisation study (PAS) register Additional monitoring *video clip Some post authorised medicines are monitored even more intensively than others additional monitoring. Easily identified by an inverted black triangle symbol displayed in the package leaflet and in the information for HCPs called the summary of product characteristics, together with a short sentence explaining what the triangle means: ▼ This medicinal product is subject to additional monitoring Medicines are placed under additional monitoring because there is less information available on it than on other medicines, e.g because it is new to the market or there is limited data on its long-term use. It does not mean that the medicine is unsafe. REF: Good Pharmacovigilance Practices Module X – Additional Monitoring. Periodic Safety Update Reports (PSUR) PSURs are pharmacovigilance documents intended to provide an evaluation of the risk- benefit balance of a medicinal product at defined time points after its authorisation. Objective is to present a comprehensive and critical analysis of the risk-benefit balance of the product Takes into account new or emerging safety information in the context of cumulative information on risk and benefits EMA and national competent authorities assess information in PSURs to determine if there are new risks identified for a medicine and/or if its risk-benefit balance has changed. PSUR assessment can determine if further investigations on a specific issue are needed, if an action is necessary to protect public health (e.g. an update of the information provided to healthcare professionals and patients). MAHs are legally required to submit PSURs Module VII of the Guidelines on Good Pharmacovigilance Practices (GVP) provides guidance on the preparation, submission and assessment of PSURs. This format is a legal requirement for both nationally authorised products and centrally authorised products. Recalls The “retrieval from the marketplace of a batch or batches of any medicinal product which is/are the subject of a quality defect”. The Market Compliance Section of the HPRA Compliance Department is responsible for co-ordinating medicinal product recalls in Ireland. Recalls of products on the Irish market occur to different levels, depending on the risk posed by the quality defect. The majority of recalls occur to retail or pharmacy level. More serious recalls occur to patient level Retrieval of a batch or batches is considered a recall once the batch(es) has been QP released and left the site of the manufacturer that QP released the batch(es) to the Irish market Different types of Recalls – See recall guidance note on HPRA Website, www.hpra.ie Batch or Product Recalls Different Levels of Recall Targeted or Blanket Recall Actions Product or Quality Defects Product defects or Quality Defects: attributes of a medicinal product or component which may affect the quality, safety and/or efficacy of the product, and/or which are not in line with the approved Product Authorisation (PA) or other marketing authorisation 3 classes of quality defects classified according to their potential risk to patient health Critical Quality Defects - defects which are potentially life-threatening or could cause a serious risk to health Major Quality Defects - defects which could cause illness or mistreatment but are not critical Minor Quality Defects - defects which may not pose a significant hazard to health http://www.hpra.ie/homepage/medicines/quality-information/sartan- recalls/valsartan-precautionary-recall Consequences of Quality Defects Remedial Actions Batch or Product Recalls Cessation of QP certification / release of the product Issuance of Caution In-Use Notifications / Dear Doctor Letters Issuance of Rapid Alert notifications to other Competent Authorities No market action, but CAPAs required Other actions – e.g. for-cause inspections by HPRA Increased regulatory oversight applied to the company More frequent inspections Increased market surveillance testing / examination work applied to the company’s products via HPRA’s Sampling & Analysis programme Recalls can occur for various reasons… For safety reasons where the product is compliant with its current MA but where the benefit-risk ratio is no longer favourable e.g. Avandia (rosiglitizanone) – increased cardiovascular risk e.g. Aulin (oral nimesulide) – liver-related safety issues As a result of quality defects/non-compliances which have safety or efficacy implications e.g. Ozurdex Eye Implant – Silicone Particulate Issue e.g. Ranitidine Tablets – Impurity (probably human carcinogen) e.g. Novomix 30 insulin pens – over and under conc. insulin e.g. Viaspan Solution - for organ preservation prior to transplant – sterility assurance concerns with one batch Other reasons… Also, some recalls are: A result of quality defects/non-compliances which have no safety implications, but have associated non-compliances e.g. Zoladex (goserelin) Implant 3.6mg, Australian packs on Irish Market with similar indications/warnings, etc. e.g. Ciprapine (citalopram) Tablets – marketing of free medical samples of this anti-depressant For purely commercial reasons – here, existing stock may be allowed to become depleted in the marketplace and then the MA is formally withdrawn by the MAH e.g. Centyl (bendroflumethiazide) 2.5mg, 5mg – various commercial manufacturing issues Recalls - Levels Where a quality defect affects a batch or batches distributed only to a limited, identifiable number of customers such as retailers, pharmacies, wholesalers, recall communications will be sent to those customers only. Where the extent of the defect is large and all customers are difficult to identify, the associated recall communications are sent to all potential customers. This is called a blanket recall. Where patient level recalls are involved, communications would typically include HPRA website and/or press statements. The Different Levels of Recalls Retail/ Patient/ 1°Wholesale 2°Wholesale Dispensing End User No Recall Recall Recall Letter Letter Recall Letter Letter Instructions to patients Free Wholesaler Medical Dear Doctor Listing from Samples Letter (DDL) 1° Wholesaler Clinical Trial Patient Stocks Clinical Trial Stocks Press statement References Pharmacovigilence http://www.hpra.ie/homepage/veterinary/regulatory-information/medicines- authorisation/pharmacovigilance-guidance-documentation http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/ http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_co ntent_000258.jsp **”Black Triangle” Video clip: https://youtu.be/qzM4NKPoovM Eudravigilence http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_co ntent_000679.jsp Recalls http://www.hpra.ie/homepage/medicines/quality-information/medicine-recalls