Introduction to Pharmacovigilance and Malaysian Adverse Drug Reaction

PPPP 2232 Pharmacoepidemiology & Pharmacoeconomics Introduction to Pharmacovigilance / Malaysian Adverse Drug Reaction ASST. PROF. DR. ZOHRA BHATTI PhD (Clinical Pharmacy) Department of Pharmacy Practice, Kulliyyah of Pharmacy, International Islamic Unive...

PPPP 2232 Pharmacoepidemiology & Pharmacoeconomics Introduction to Pharmacovigilance / Malaysian Adverse Drug Reaction ASST. PROF. DR. ZOHRA BHATTI PhD (Clinical Pharmacy) Department of Pharmacy Practice, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan Campus, Jalan Sultan Ahmad Shah, Bandar Indera Mahkota, 25200 Kuantan, Pahang  Drug Effects Positive Effects No Drugs response Negative 3 Post Marketing Surveillances (PMS) After marketing of a drug, close monitoring for unexpected adverse drug reactions (ADRs) remains necessary due to the limited size of premarketing trials, the selection of the patients involved and the limited duration of the trials Post-marketing surveillance aims at a timely detection of either new ADRs or an increase of the frequency of ADRs which are already known to be associated with the drugs involved. 4  INTRODUCTION TO PHARMACOVIGILANCE Before a product is No matter how extensive the marketed, experience of its pre-clinical work in animals safety and efficacy are limited and the clinical trials in to its use in clinical trials. patients, certain adverse The conditions under which effects may not be detected patients are studied pre- until a very large number of marketing do not necessarily people have used the reflect the way the product will medicinal product. be used in hospitals or in general practice once it is marketed. 5 DEFINITION OF PHARMACOVIGILANCE (PV) Pharmacovigilance (PV) is defined as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem”. World Health Organization. (2002). Safety of medicines: a guide to detecting and reporting adverse drug reactions. Geneva: World Health Organization, 20. 6 In line with this definition, the objectives of pharmacovigilance are: To identify To prevent To assess To promote previously harm from the risks and the safe and unrecognized adverse reactions benefits of effective use of adverse reactions arising from the use products in order medicinal or changes in the of medicinal to determine what products, through patterns of adverse products actions, if any, are providing timely effects necessary to information about improve their safe the safety of use medicinal products to patients, healthcare professionals and the public 7  DEFINITION OF ADVERSE DRUG REACTIONS (ADRs) ADR is defined as “a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modifications of physiological function” World Health Organization. (1972). International drug monitoring: the role of national centres, report of a WHO meeting [held in Geneva from 20 to 25 September 1971]. World Health Organization.8  DEFINITION OF ADVERSE DRUG EVENTS (ADEs) An injury resulting from the use of a drug Can occur irrespective of whether or not the drug is suspected to be the cause Nebeker, J. R., Barach, P., & Samore, M. H. (2004). Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting. Annals of internal medicine, 140(10), 795-801.9  ADRs vs ADEs The main difference whereas ADE is harm between these terms is associated with any dose that ADR is a harm of a drug, whether or not usually suspected to be the dose is “normally used related to the drug and in man” or due to other may occur despite the confounders that arise appropriate prescribing during treatment but are and dosing. not necessarily caused by the pharmacology of the drug itself AlAzmi, A., Ahmed, O., Alhamdan, H., AlGarni, H., Elzain, R. M., AlThubaiti, R. S.,... & Al Shaikh, A. (2019). Epidemiology of Preventable Drug-Related Problems (DRPs) Among Hospitalized Children at KAMC-Jeddah: a Single-Institution Observation Study. Drug, Healthcare and Patient Safety, 11, 95. 10 Development of Pharmacovigilance as a Discipline Origins: Pharmacovigilance traces its roots back to the mid-20th century when researchers began recognizing the need for systematic monitoring of adverse drug reactions (ADRs). Thalidomide Tragedy: The thalidomide disaster of the 1950s and 1960s, where the drug caused severe birth defects, served as a wake-up call for the necessity of pharmacovigilance. This incident highlighted the importance of post-marketing surveillance to detect rare but serious ADRs. 6/29/2024 11 Development of Pharmacovigilance as a Discipline: Regulatory Responses: In response to the thalidomide tragedy, regulatory agencies worldwide started implementing pharmacovigilance systems to monitor drug safety more effectively. This led to the establishment of formal pharmacovigilance programs in many countries 10/11/2020 12 Milestones in Pharmacovigilance History WHO Program: The World Health Organization (WHO) initiated its Programme for International Drug Monitoring in 1968. This program aimed to facilitate the exchange of information on ADRs among member countries and promote collaboration in pharmacovigilance activities. Pharmacovigilance Guidelines: Various international bodies, such as the International Conference on Harmonisation (ICH) and the Council for International Organizations of Medical Sciences (CIOMS), developed guidelines and standards for pharmacovigilance practices. These guidelines provide a framework for the systematic monitoring and reporting of ADRs. 6/29/2024 13 Rawlins and Thompson classification of adverse drug reactions Since the 1970s, ADRs have traditionally been classified into two broad categories: Types A and B. The usual characteristics of these different types of reactions are contrasted, followed by some examples: Type A (Augmented) reactions: Dose‐related; Predictable from drug pharmacology; Common; Reversible; Manageable with dose adjustment. Classic examples of Type A reactions are Bleeding (warfarin), hypoglycaemia(anti‐diabetic agents) & headache (nitrates) 14  TYPES of adverse drug reactions Type B (Bizzare) reactions: Not dose‐related; Unpredictable; Uncommon; Serious irreversible; Indicative that the drug needs to be stopped. Classic examples of Type B reactions are Anaphylaxis (penicillins), hepatitis (halothane) & agranulocytosis (clozapine) Additional categories of ADRs Type C (Chronic), e.g. adrenal suppression with corticosteroids. Type D (Delayed), e.g. tardive dyskinesia with neuroleptics. Type E (End of use), e.g. withdrawal reactions with benzodiazepines 15  DoTS Classification In 2003, a system of classification was proposed by Aronson and Ferner based on dose‐relatedness, time course and susceptibility; DOSE TIME SUSCEPTIBLITY Toxic Independent Age Collateral Dependent Gender Hyper susceptibility rapid administration Ethnic origin First dose Genetic disease Delayed Withdrawal Early, intermediate, late 16 DoTS Classification  DoTS classification is more The classification system categorizes complete as it allows the ADRs into five types, each representing a evaluation of ADRs different aspect of the relationship between according to the dose used of the drug and the adverse event: the suspect drug, the time between ADR occurrence and Type I (Dose-Related) the drug administration (consumption), for reactions Type II (Time-Related) that are time-dependent, and Type III (Susceptibility-Related) the relationship with different Type IV (Withdrawal-Related) susceptibility factors that determine an increased risk of Type V (Unexpected Failure of Therapy). adverse reactions. 17  DoTS Classification Example Osteoporosis due to corticosteroids: this reaction occurs at therapeutic doses, usually after some months of treatment. Females and older people are at the greatest risk. Hence, it would be classified as: Dose: collateral effect Time: late Susceptibility: age, sex Significance of DOTS approach The DOTS approach is useful because it addresses the limitations of the Type A/B scheme into which many ADRs do not clearly fit. 18  ADR REPORTING SYSTEM 6/29/2024 19  MADRAC, DCA & NPRA Malaysia set up its national pharmacovigilance system with the establishment of the Malaysian Adverse Drug Reactions Advisory Committee (MADRAC) in 1987. MADRAC acts as an advisory body to the Drug Control Authority (DCA) on local and international drug safety issues. The National Adverse Drug Reaction Monitoring Centre, located within the National Pharmaceutical Regulatory Agency (NPRA) serves as the secretariat to MADRAC, and has been a member of the WHO Programme for International Drug Safety Monitoring since 1990. What MADRAC do? Promote ADR reporting in Malaysia Provide information and advice to the DCA in order that regulatory action can be taken based on the ADRs received (local & foreign). Provide information to doctors, pharmacist and other health care professionals on ADRs. Participate in the WHO ADR monitoring programs. 21 Pharmacovigilance System One of the pharmacovigilance requirements for pharmaceutical companies is the establishment of a pharmacovigilance system within their organizations. Pharmaceutical companies need to ensure their pharmacovigilance systems are up to standards as any deficiencies may impact patient safety. 23 Pharmacovigilance Evaluating Methods Spontaneous ADR Reporting. Prescription Event Monitoring (PEM). Case–Control and Case–Crossover Studies. Cohort Studies. Randomized Controlled Trials. 27 Spontaneous reporting system (SRS) The core data-generating system of international Pharmacovigilance, relying on healthcare professionals (and in some places consumers) to identify and report any suspected adverse drug reaction to their national Pharmacovigilance center or to the manufacturer. 28  Spontaneous reporting system (SRS) Advantages Early detection of signals of new , rare or serious ADRs. Primary mechanism for generating suggestions regarding potential ADRs, (hospital and out-patient care). Operates for all drugs through out the whole of their lifetime. Disadvantages Under reporting. The term underreporting is predominantly used to indicate that not all the adverse effects that occur are reported. Variable qualities of reporting. Data from the SRS, when taken alone, do not accurately quantify the risk associated with a drug. 29 Prescription Event Monitoring (PEM) A method used for the systematic collection and evaluation of data on the safety and effectiveness of newly marketed drugs in real-world clinical practice. The primary purpose of PEM is to detect and assess adverse reactions or events associated with newly marketed drugs that may not have been identified during pre-marketing clinical trials. Pharmacists or other healthcare providers collect information from patient prescription forms or electronic records, including demographic details, prescribing patterns, and adverse events reported by patients or healthcare professionals. 6/29/2024 30  Findings from PEM studies are reported to regulatory agencies, pharmaceutical companies, healthcare professionals, and the scientific community through publications. Advantages: It complements data from pre-marketing clinical trials by capturing ADRs that may occur at lower frequencies or have delayed onset. Additionally, PEM allows for the assessment of drug utilization patterns, adherence to prescribing guidelines, and potential off-label use. Disadvantages: including potential underreporting of adverse events, biases in patient selection and follow-up, reliance on healthcare providers for data collection, and challenges in establishing causality between drug exposure and adverse reactions. 6/29/2024 31 ADR reporting by Case–Control and Case–Crossover Studies case-control and case-crossover studies are not typically used for direct ADR reporting, they can indirectly contribute to the understanding of ADRs by investigating the association between exposure to a particular drug and the occurrence of adverse events. Instead, they contribute to the broader field of pharmacoepidemiology by generating evidence on the safety profile of drugs and identifying potential ADRs that require further evaluation through systematic ADR reporting systems, such as spontaneous reporting programs, pharmacovigilance databases, and clinical trials. 6/29/2024 32 ADRs Reporting by COHORT STUDIES Cohort studies are a valuable tool for ADR reporting and pharmacovigilance, as they provide longitudinal data on drug exposure and adverse events in a defined population over time. Cohort studies involve the prospective follow-up of a group of individuals who are exposed to a particular drug or medication regimen and a comparison group of unexposed individuals. 6/29/2024 33 ADRs reporting by Randomized Controlled RCTs are primarily designed to assess the efficacy of medications, they also play a crucial role in ADR reporting and pharmacovigilance by providing valuable data on the safety profile of drugs in controlled clinical settings. By systematically collecting and analysing data on adverse events, RCTs contribute to the ongoing evaluation of drug safety and help ensure the safe and effective use of medications in clinical practice. 6/29/2024 34 Scope of Pharmacovigilance in Malaysia The scope of pharmacovigilance in Malaysia includes (but is not limited to): 2. Safety profile monitoring through 1. ADR/AEFI reporting by healthcare signal management process, as well as professionals, consumers and PRH, preparation and evaluation of Periodic collection of reports and monitoring by Benefit-Risk Evaluation Report PRH and the Authority. (PBRER) and Risk Management Plan (RMP). 4. Safety communication, for example 3. Risk Management System: a set of Direct Healthcare Professional pharmacovigilance activities and Communication (DHPC) Letter, interventions designed to identify, Package Insert (PI), websites, characterise, prevent or minimise risks publications and Consumer Medication relating to a medicinal product, Information Leaflet (RiMUP); to ensure including the assessment of the product information is updated with effectiveness of those interventions. latest safety information according to NPRA directives and circulars. REPORTING OF ADVERSE DRUG REACTION (ADR) AND ADVERSE EVENT FOLLOWING IMMUNISATION (AEFI) Information from the spontaneous Information from all these ADR/AEFI reporting schemes, in sources may lead to the following combination with clinical and regulatory changes/actions: epidemiological studies as well as a) Restriction in usage; literature, are used to aid in the b) Refinement of dosage decision-making on product instructions; safety. c) Strengthening of specific warnings; All reports submitted to NPRA are d) Reviewing of specific labelling treated as confidential and requirements; reporters are not required to e) Changes in product information divulge the identity of the based on new findings; patient(s) involved. Scope of ADR Reporting The WHO encourages reporting of all suspected ADRs. Healthcare A reaction is suspected if the provider, product registration holder reporting healthcare professional, (PRH ) and consumer are requested to report ADRs suspected to be PRH or any person who possesses related to all products registered with any registered product(s) believes the Drug Control Authority (DCA), that there is a possible causal e.g. pharmaceutical products relationship between the reaction including biologics, over–the and the product in question. If so, all counter (OTC) products, health available relevant clinical supplements, and natural products, information must be provided. even for common/minor or well- documented reaction. Scope of ADR Reporting (Cont.) All adverse reactions should Adverse events, which are not be considered reportable suspected of being product- according to the requirements related by the healthcare outlined in this guideline professional attending to the regardless of whether or not patient, should not be reported the product was used in UNLESS the PRH feels that accordance with the product there is a possible causal information provided by the relationship between the PRH. reaction and the product in question. Scope of ADR Reporting (Cont.) As for regulatory reporting ADR(s) due to OTC product(s), purposes, if an event is health supplement(s) and natural product(s) spontaneously reported, even if ADR(s) related to any suspected the relationship is unknown or forms of drug interactions e.g. drug- unstated, it should meet the drug, drug-food interactions, etc. definition of an adverse drug Change in frequency of a known reaction. ADR(s). In ADR reporting, priority should ADR(s) involving special patient populations, e.g. pregnant, be given in the following breastfeeding, elderly or paediatric categories: patients. Serious ADRs Unexpected/unlabeled ADRs for all new and generic products. Scope of AEFI Reporting An AEFI is any untoward Monitoring of AEFI is an medical occurrence which effective way to monitor follows immunisation and immunisation safety and which does not necessarily contributes to the credibility of have a causal relationship with National Immunisation the usage of the vaccine. Programme (NIP). The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease. Scope of AEFI Reporting (Cont.) All AEFI should be reported: Non-serious AEFI – An AEFI that is not ‘serious’ and does not pose a potential risk to the health of the recipient. Serious AEFI – An event that either results in death, is life- threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defects. Any medical event that requires intervention to prevent one of the outcomes listed above may also considered as serious. 5 categories of AEFIs 5 categories of AEFIs (Cont.) https://www.npra.gov.my/index.php/en/consumer- medication-information-leaflets-rimup.html https://www.pharmacy.gov.my/v2/en/documents/malaysian -orphan-medicines-guideline-2020.html GENERAL PRINCIPLES OF ADR/AEFI SUBMISSION The following are ADR/AEFI reporting forms available in Malaysia. The related forms can be found in (Appendix 1) 1.. Online reporting form 3. Consumer Side Effect Reporting Form Available via (ConSERF) https://npra.gov.my/index.php/en/health- For the general public professionals/reporting-adr.html 4. Borang Pemantauan Kesan Advers Ringan Susulan Imunisasi 2. Report on Suspected Adverse Drug Specifically for parents or guardian or Reactions vaccinees for minor AEFI Prepaid reporting blue form 5. Suspect Adverse Reaction Report Form (CIOMS Form I) For PRHs Example of Online reporting form Example of Manual Form 6/29/2024 53 6/29/2024 54 CIOMS FORM 6/29/2024 55 PCNE Classifica tion for Drug- Related Problems www.pcne.o rg 10/11/2020 56  57 PHM 3113 From ADR Report to Drug Policy Assessment Receive ADR Verify WHO report/information information Requires Discuss at Prepare policy regulatory MADRAC paper for DCA action? meeting IMPLEMENT POLICY PHM 3113 58 well, to maintain within the desired range Verily those who say, "Our Lord is Allah," and remain firm (on that Path),- on them shall be no Al- fear, nor shall they grieve. Ahqaaf 46:13 SOME OF THE DEFINITIONS 6/29/2024 65