MEDCLINIGEN Pharmacovigilance.pdf

MEDCLINIGEN ACADEMY MEDCLINIGEN ACADEMY PHARMACOVIGILANCE ADVANCED STUDY MATERIAL 1|P a ge MEDCLINIGEN ACADEMY CONTENTS 1. HISTORY & INTRODUCTION OF PV 2. NEED FOR PHA...

MEDCLINIGEN ACADEMY MEDCLINIGEN ACADEMY PHARMACOVIGILANCE ADVANCED STUDY MATERIAL 1|P a ge MEDCLINIGEN ACADEMY CONTENTS 1. HISTORY & INTRODUCTION OF PV 2. NEED FOR PHARMACOVIGILANCE 3. BASIC CONCEPTS & TERMINOLOGIES OF PV 4. KEY GUIDELINES THAT COLLABORATE WITH PV 5. PV PROCESS - OVERVIEW 6. CHALLENGE CONCEPTS IN PV 7. CAUSALITY ASSESSMENT 8. ICSR & PROCESSING TOOLS 9. ADR REPORTING SYSTEMS OF DIFFERENT COUNTRIES 10. AGGREGATE REPORTS 11. OPPORTUNITIES IN PV/ DRUG SAFETY 12. FAQS 2|P a ge MEDCLINIGEN ACADEMY Where does PHARMACOVIGILANCE starts? Step 6: FDA Step 1: Drug Step 2: Step 3: Clinical Step 4: FDA Post-Market Step 5: Scaleup Discovery Preclinical Research Review FDA Manufacturing & Surveillance Research Drugs are tested review Sales and FDA monitors Research for on people to teams all drug and Drugs marketing a new drug undergo make sure they thoroughly device safety begins in the are safe and examine all of laboratory and effective once products laboratory animal testing the submitted are available Phase 1: PK, Ligant & to answer dose range & data related to for use by the target , basic Safety in the drug or public identification questions healthy subjects device and On-going Phase 2: make a Pharmacovigila s with their about safety nce in all IND with Efficacy with decision to interaction dose range & approve or broader clinical Formulation, population Safety in not to ADME, patients Phase Toxicity, approve it 3: Efficacy in Mechanism & large patients & Efficacy NDA submission 3|P a ge MEDCLINIGEN ACADEMY 1. INTRODUCTION AND HISTORY OF PV 1848 1893 1906 15 year of died in course of Lancet initiated foundation of US federal Food and Drug Act – required, that the pharmaceuticals routine anesthesia with commission and starting should be ‘pure’ and ‘free from chloroform (problem: collection of notifications any contamination’ (nothing about fibrillation of ventricles?) about side effects efficacy) 1938 1961 Food, Drug, and Cosmetic Act, 1936 1938. Firms had to prove to Thalidomide disaster – FDA that any new drug was USA-s 107 lethal cases phocomelia safe before it could be post sulfanilamides marketed 1965 First EU pharmaceutical 1968 directive – aimed to establish Start of WHO program for 1990 and maintain high level of international drug ICH safety guidelines protection for public health in monitoring Europe 4|P a ge MEDCLINIGEN ACADEMY THALIDOMIDE TRAGEDY Thalidomide was first marketed in the late 1950s as a sedative and was used in the treatment of nausea in pregnant women Within a few years of the widespread use of thalidomide in Europe, Australia, and Japan, approximately 10,000 (between 1957and 1962) children were born with “phocomelia” (a rare condition that causes very short limbs), leading to the ban of thalidomide in most countries in 1961.  In addition to limb reduction anomalies, other effects included congenital heart disease, malformations of the inner and outer ear, and ocular abnormalities. The thalidomide disaster completely changed the way drugs are tested. It was prescribed as a totally safe sedative and was used in treatments for flu and also the morning sickness and insomnia associated with pregnancy, despite the fact that no safety testing had been done on pregnant animals. It is sometimes argued that, in the 1950s, no new medicines were tested in pregnant animals because scientists did not yet understand that the foetus could be damaged by external factors. 5|P a ge MEDCLINIGEN ACADEMY SULFANILAMIDE TRAGEDY: Sulfanilamide is a drug used to treat streptococcal infections, during September and October 1937 this drug is responsible for deaths of more than 100 people in 15 states. The drug and deatrhs led to passage of 1938 food drug and cosmetic act, which increased FDA’s authority to regulate drugs. In 1937, S. E. Massengill Company, a pharmaceutical manufacturer, created an oral preparation of sulfanilamide using diethylene glycol (DEG) as the solvent or excipient, and called the preparation "Elixir Sulfanilamide". DEG is poisonous to humans and other mammals, but Harold Watkins, the company's chief pharmacist and chemist, was not aware of this. (Although the first case of a fatality from the related ethylene glycol occurred in 1930 and studies had been published in medical journals stating DEG could cause kidney damage or failure, its toxicity was not widely known prior to the incident.) Watkins simply mixed raspberry flavoring into the powdered drug and then dissolved the mixture in DEG. Animal testing was not required by law, and Massengill performed none; there were no regulations at the time requiring premarket safety testing of drugs. 6|P a ge MEDCLINIGEN ACADEMY 2. BASIC CONCEPTS OF DRUG SAFETY What is Pharmacovigilance? Definition: The World Health Organization (WHO) describes pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem. This includes: – Collection and evaluation of spontaneous case reports of suspected adverse events – Pharmaco-epidemiological studies (ICH 2004). No medicine is absolutely safe, and all pose some magnitude of safety and health risks Making sure that medicines are safe for their intended use is an ongoing process that starts in the developmental stage and continues long after medicines in the market Pharmacovigilance derived from Pharmakon (Greek) = Medicine/drug Vigiare (Latin) = Watchfulness/to keep watch. Aims and Objectives of PV The specific aims of pharmacovigilance are to: Improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions; Improve public health and safety in relation to the use of medicines; Detect problems related to the use of medicines and communicate the findings in a timely manner; Contribute to the assessment of benefit, harm, effectiveness and risk of medicines, leading to the prevention of harm and maximization of benefit; Encourage the safe, rational and more effective (including cost-effective) use of medicines; Promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public. 7|P a ge MEDCLINIGEN ACADEMY Products covered by Pharmacovigilance Medicines Herbal, traditional & supplements Biologics Blood products Vaccines Medical devices Cosmetics Veterinary Tabaccovigilance 8|P a ge MEDCLINIGEN ACADEMY Current Practice The success or failure of any pharmacovigilance activity depends on the reporting of suspected adverse reactions Spontaneous reporting: The definition of spontaneous reporting is as follows: “A system whereby case reports of adverse drug events are voluntarily submitted by health professionals and pharmaceutical companies to the national pharmacovigilance center.” Other methods of collecting safety data: A number of countries have implemented active surveillance systems to complement spontaneous reporting. Examples of such systems are: Prescription event monitoring (PEM) in New Zealand and the United Kingdom; record linkage; case-control studies. National pharmacovigilance centers: National pharmacovigilance centers are responsible for: Promoting the reporting of ADRs; collecting case reports ADRs; clinically evaluating case reports; collating, analyzing and evaluating patterns of ADRs; distinguishing signals of adverse reactions from “noise”; recommending or taking regulatory action in response to findings supported by good evidence; initiating studies to investigate significant suspect reactions; alerting prescribers, manufacturers and the public to new risks of adverse reactions; and sharing their reports with the WHO program for international drug monitoring WHO Program for International Drug Monitoring: It plays a key role as a communication and training center and clearing-house for information on the safety of medicines. The WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden manages the international database of adverse reaction reports received from national centers 9|P a ge MEDCLINIGEN ACADEMY Key Stakeholders in Pharmacovigilance Patients and patient organisations (PO) -POs work with some NCAs to facilitate adverse reaction reporting; number of POs involved per Member State varies from 1 to 20 Health care professionals (HCP) (Doctors, pharmacists, nurses and all other professionals working with medicines) -are members of PRAC; participate in all activities of the Committee; supply relevant perspectives to all aspects of its work Pharmaceutical industry or individual marketing authorization holders (MAHs) -MAHs are responsible for collecting, reviewing and analyzing information on suspected adverse reactions received via patients, healthcare professionals, scientific literature, clinical trials and studies or other sources Regulators such as Authorities, Ethics committees. E.g. European Commission (EC), National Competent Authorities (NCAs), Pharmacovigilance Risk Assessment Committee (PRAC) 10 | P a g e MEDCLINIGEN ACADEMY Few Important Terminologies In PV Side Effect Adverse event (AE) Adverse Drug Reaction (ADR) Serious Adverse Event (SAE) Serious, unexpected suspected adverse reaction (SUSAR) Side-effect (SE): A side effect is an undesired effect that occurs when the medication is administered regardless of the dose. Unlike adverse events, side effects are mostly foreseen by the physician and the patient is told to be aware of the effects that could happen while on the therapy. Side effects differ from adverse events and later resolve on their own with time after taking the medication for several weeks. Common side effects include upset stomach, dry mouth, and drowsiness, diarrhea, dizziness, drowsiness, fatigue, heart issues (palpitations, irregular heartbeats), hives, and nausea Adverse Event [AE]: “Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment”. The event can either be a type A reaction or a type B reaction. Type A reactions are predictable adverse events which are commonly dose dependent and can be mild, moderate, or severe. Type B reactions are completely unpredictable and have nothing to do with doses. Adverse Drug Reaction (ADR): “Any noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions which necessarily have to have a causal relationship with this treatment.” Examples of such adverse drug reactions include rashes, jaundice, anemia, kidney damage, and nerve injury that may impair vision or hearing Serious Adverse Event (SAE): An adverse event that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. 11 | P a g e MEDCLINIGEN ACADEMY Unexpected Adverse Drug Reaction: “An adverse reaction, the nature or severity of which is not consistent with the applicable product information” Blinding/Masking: A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Singleblinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s). Company Core Data Sheet (CCDS): “This document is prepared by the Marketing Authorization Holder and contains, in addition to safety information, material relating to indications, dosing, pharmacology and other aspects of the product” Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice. Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials. Off-label use: This relates to situations where the medicinal product is intentionally used for a medical purpose not in accordance with the authorized product information. Triage refers to the process of placing a potential adverse event report into one of three categories: 1) Non-serious case; 2) Serious case; or 3) No case (minimum criteria for an AE case are not fulfilled). Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post marketing trial to study the issue. Marketing Authorization Holder: Any company, firm or non-profit organization, which holds a marketing authorization granted by the European Medicines Agency (EMA), is called a Marketing Authorization Holder (MAH). An MAH is allowed to distribute and sell its medicinal products in one or more European Union (EU) member states. 12 | P a g e MEDCLINIGEN ACADEMY Grades of Adverse Events Grade 5 Grade 4 Grade 3 Grade 2 Grade 1 Adverse events are graded on a scale from 0 to 5. Grade 0 refers to not having any symptom or problem, so someone with grade 0 pain has no pain at all Grade 1: Mild, asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate, minimal, local or noninvasive intervention indicated Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization and intervention indicated Grade 4: Life-threatening consequences, urgent hospitalization and intervention indicated. Grade 5: Death related to AE/fatal. 13 | P a g e MEDCLINIGEN ACADEMY Types of ADRs Type A Type B Type C Type D Type E Type F (Augmented) (Bizarre) (Chronic) (Delayed) (End of use) (Failure) Mechanisms of ADRs TYPES CHARACTERISTICS EXAMPLES Dose-dependent, frequent, predictable, drug overdose, Bleeding after anticoagulants; A - Augmented explained by pharmacologic hypoglycemia from insulin drug effect Dose-independent, rare, Urticaria/asthma from aspirin; B - Bizarre unpredictable, not explained by exanthem from antibiotic pharmacologic drug effect Dose and time dependent, rare, Paracetamol hepatotoxicity; C - Chronic long-term exposure Cushing syndrome from cortisone Kidney disease from long-term D -Delayed Time dependent, very rare analgesics or (NSAIDs); bladder carcinoma with Cyclophosphamide. Withdrawal effects of drugs (e.g. Time dependent, rare, relapse opioids or antiepileptics), rebound E -End of treatment after stopping a therapy or relapse phenomena; Seizures after stopping Phenytoin 14 | P a g e MEDCLINIGEN ACADEMY 3. Key Guidelines That Collaborative With PV WHO ICH CIOMS PV Regulations And Guidelines ICH The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe, Japan and the United States to discuss scientific and technical aspects of pharmaceuticals and develop ICH guidelines. Regulatory harmonization offers many direct benefits to both regulatory authorities and the pharmaceutical industry with beneficial impact for the protection of public health. Key benefits include:  Preventing duplication of clinical trials in humans and minimizing the use of animal testing without compromising safety and effectiveness; Streamlining the regulatory assessment process for new drug applications; Reducing the development times and resources for drug development. ICH Guidelines This regulatory harmonization is achieved by developing guidelines. These guidelines are divided into four categories as follows: Q – Quality Guidelines: Defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management. S – Safety Guidelines: ICH has produced a comprehensive set of safety guidelines to uncover potential risks like carcinogenicity, genotoxicity and reproductive toxicity. E – Efficacy Guidelines: The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, and safety and reporting of clinical trials. M – Multidisciplinary Guidelines: Those are the cross-cutting topics which do not fit uniquely into one of the Quality, Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA) and the Common Technical Document. 15 | P a g e MEDCLINIGEN ACADEMY Q – Quality S – Safety S1-12 Q1-14 E – Efficacy M– Multidisciplinary E1-20 M1-14 ICH PV Guidelines 16 | P a g e MEDCLINIGEN ACADEMY Council for International Organizations of Medical Sciences (CIOMS) In 1986, CIOMS set up its first Working Group on pharmacovigilance, a Working Group on International Reporting of Adverse Drug Reactions to explore means of coordinating and standardizing international adverse drug reporting by pharmaceutical manufacturers to regulatory authorities. Its agenda was limited to post-marketing reporting of adverse drug reactions occurring in one country and which the pharmaceutical industry should report to regulatory authorities in other countries where the drug is also marketed. CIOMS is an international, non-governmental, non-profit organization established jointly by WHO and UNESCO in 1949 to serve the scientific interests of the international biomedical community. In 1949, Council formally constituted in Brussels by WHO and UNESCO. In 1952, present name CIOMS adopted. In 1959, Vienna meeting on controlled clinical trials. In 1977, Launch of Ethics of Research involving humans. In 1982, Adoption by UN of CIOMS Medical Ethics for prisoners. In 1993, Start of CIOMS focus on pharmacovigilance and reporting adverse drug reactions. In 2016, New CIOMS Ethical Guidelines for Health-related research involving humans. 17 | P a g e MEDCLINIGEN ACADEMY Type Context CIOMS I The international reporting form CIOMS II Periodic safety update reports CIOMS III Core data sheets CIOMS IV Benefit-risk assessments CIOMS V Practical issues in Pharmacovigilance CIOMS VI Clinical trial safety data CIOMS VII Development safety update reports Pharmacovigilance Regulatory Bodies Country Regulatory Authority Australia Therapeutic Goods Administration (TGA) Brazil ANVISA Pharmacovigilance Unit (Federal Agency) Canada Health Canada China China Food and Drug Administration France ANSM( AgenceNationale de SécuritéduMédicament et des produits de Santé) Germany BundesinstitutfuerArzneimittel und Medizinprodukte (BfArM)or also known as Federal Institute for Drugs and Medical Devices India Drugs Controller General (India) Italy Italian Pharmaceutical Agency Ministry of Health Hong Kong Department of Health: Pharmaceutical Services Japan Pharmaceuticals and Medical Devices Agency (PMDA) New Zealand New Zealand Medicines and Medical Devices Safety Authority Singapore Health Sciences Authority (HSA) Sweden Medical Products Agency (MPA) UK Medicines and Healthcare products Regulatory Agency (MHRA) US U.S. Food and Drug Administration (US FDA) 18 | P a g e MEDCLINIGEN ACADEMY Guideline on Good Pharmacovigilance Practices Good pharmacovigilance practices (GVP) guidelines GVP Module I: Pharmacovigilance systems and their quality systems GVP Module II: Pharmacovigilance system master file (Rev. 2) GVP Module III: Pharmacovigilance inspections GVP Module IV: Pharmacovigilance audits (Rev. 1) GVP Module V: Risk management systems (Rev. 2) GVP Module VI: Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2) GVP Module VI (Addendum I): Duplicate management of suspected adverse reaction reports GVP Module VII: Periodic safety update report GVP Module VIII: Post-authorisation safety studies (Rev. 3) GVP Module VIII Addendum I: Requirements and recommendations for the submission of information on noninterventional post-authorisation safety studies (Rev. 3 new text first published) GVP Module IX: Signal management (Rev. 1) GVP Module IX: Addendum I: Methodological aspects of signal detection from spontaneous reports of suspected adverse reactions GVP Module X: Additional monitoring GVP Module XV: Safety communication (Rev. 1) GVP Module XVI: Risk minimization measures: selection of tools and effectiveness indicators GVP Module XVI: Addendum I: Educational materials 19 | P a g e MEDCLINIGEN ACADEMY ICSR (INDIVIDUAL CASE SAFETY REPORT) Individual Case Safety Report is 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. 20 | P a g e MEDCLINIGEN ACADEMY 21 CFR for PV The Code of Federal Regulations (CFR) is a codification of the general and permanent rules published in the Federal Register by the Executive departments and agencies of the Federal Government Title 21 of the CFR is reserved for rules of the Food and Drug Administration PART 312 - INVESTIGATIONAL NEW DRUG APPLICATION 21 CRF part 312.32 - IND safety reporting 21 CRF part 312.33 - Annual reports Part 314 - APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG 21 CRF part 314.80 - Post marketing reporting of adverse drug experiences 21 CRF part 314.81 - Other post marketing reports. Regulatory Reporting of Adverse Reactions Why to report? Ethical requirement Regulatory requirement Legal requirement Who reports? Company (post marketing) Company and investigator joint responsibility (clinical trials) When to report? Expedited – 7 to 15 calendar days Periodic – depending upon when launched / region What to report? Patient details, Suspected drug details, Other treatments, Details of suspected ADR, Outcome, Details of reporter 21 | P a g e MEDCLINIGEN ACADEMY Drug Safety – Sources of Information Pre-marketing (During Development) Pre-clinical (animal / in-vitro) studies Clinical studies – Phase I – III Post-marketing Spontaneous adverse reaction reporting Regulatory authorities Contractual partners Published medical literature Clinical trials - PMS & Phase IV studies, epidemiological studies Data collected for other purposes 4. Pharmacovigilance Process Overview 22 | P a g e MEDCLINIGEN ACADEMY Case Data Quality Medical Submis Receipt Triage Control Review Entry sion 1. Log in 1. Case 1. Case data 1. Accuracy 1. Review of 1. All data sets validation for entry into & quality for event term documents received in min reporting safety data entry selection & including the form of request database against source narrative text medwatch , fax, email, 2. Medical along with the document. followed by CIOMS for call reports review source 2. Removal of required post marketing 2. Check for assessment of documents duplicate modifications cases are duplicacy as the case for 2. Coding of records. if necessary. gathered & fresh case or serious criteria concomitant 3.review of 2. Review of submitted to follow up 3. Source data medication in meddra term AEA regulatory case verification of the WHO selection for expectedness. dept. For 3. Assign a cases received drug verbatim 3. submission. unique ID for within 24 hrs. dictionary terms Identification 2. For clinical searching/ Of the receipt 3. Writing for 4. Review of of similar trial cases, the tracking - patient a narrative narrative text events for analysis of purpose - reporter text & required expedited similar events - drug 4. Verbatim modifications reporting. & investigator - ADE terms coding according to 4. For letters are 4.Identification as per meddra narrative expedited included with and routing of and WHO template. cases, an the submission cases based on 5. Coding of 5.checking of investigator documents. serious criteria labs and lab labs & lab letter is written 3. Submissions - non results are values & signed by are recorded serious entered. 6. Triage the physician. and tracked in - serious Queries are assessment & 5. Final the safety - NO case generated and up gradation medical review database. sent of case if & sign off. necessary. 7. Assessment for expectedness of AE according to product inserts. 23 | P a g e MEDCLINIGEN ACADEMY Narrative Writing In PV Objective The objective of the narrative is to summarize all relevant clinical and related information, including patient characteristics, therapy details, prior medical history, clinical course of the event(s), laboratory evidence and any other information that supports or refuses a diagnosis for an ADR. The information should be presented in a logical time sequence Regulatory Perspective The ICH guideline (E2B) on data elements and specifications for electronic reporting of individual ADR cases states that company narratives are required for all serious reactions. Narratives are expected to be submitted for all cases reported expeditiously to any regulatory authority, but are useful and should be made available when needed for other types Of reports and purposes. Report type and reporter information Patient demographics Patient medical history and concomitant medication information Suspect product information timing and conditions surrounding the onset of the reaction(s) Clinical course of the events, with an indication of timing of event corresponding to drug administration Nature, intensity/severity, and outcome of the event Relevant laboratory findings Treatment administered for the event Flow of Action taken With respect to the drug Dechallenge and rechallenge information, if applicable Narrative: Postmortem findings (if applicable) Outcome of event. Clinical relation of event With suspect drug The original reporter's clinical assessment The narrative preparer's (sponsor's) medical evaluation and comment. 24 | P a g e MEDCLINIGEN ACADEMY Sample Narrative Writing Narrative Outline: A narrative is written with these sentences coming one after another in the following order. Please give special attention to the order of these sentences. 1) Subject ID (most serious adverse event/events): 2) This age-year-old ethnicity man/woman had a medical history of XXXXX. Including past history and history at the time of the start of the trial. 3) Upon study admission, the subject was noted to have XXXXX. The reason he/she is being treated with the study drug. 4) He/She was randomly assigned to treatment with XXXXX. Study drug and dosing regimen, 5) A description of the most serious adverse event (e.g. prolonged hospitalization or death) including the day it started, its effect and the action taken (e.g. withdrawal of treatment or change in dosing regimen) if any. 6) A description of the nature (intensity) and relationship of this event to the study medication, e.g., not related/possibly related/related to the study medication. (causality information) 7) The treatment used for this event and the outcome (resolved, persisted, etc.) If death was the most serious event, this sentence is not necessary 8) Other adverse events are listed and relation of these adverse events and their outcomes are given too. 9) List and description of laboratory results/vital signs which are related to the serious adverse event/events and their outcome and/or a statement stating that no significant lab values/vital signs were reported. 10) The last sentence as statement, “The subject completed the study on Day X or The study was terminated on Day X due to XXXXX”. 25 | P a g e MEDCLINIGEN ACADEMY Safety Data Processing - ICSR Special situations in ICSR Special situations are non-standard medical conditions that provide valuable information (e.g., clinical safety) about medicinal product, event when they do not occur in association with an adverse event or medical condition; therefore, should be recorded/reported/ monitored for:  Complying with regulatory guidelines (e.g. ICH, FDA, EMA)  Meeting protocol specific requirements  Continuous benefit-risk assessment of medicines Examples of AEs of special situation:  Pregnancy  Lack of efficacy  Overdose  Abuse/misuse of medication  Off-label use  Medication er 5. Challenge Concepts In PV Challenges These concepts are frequently used in the discussion of causality and regulatory agencies pay particular attention to them in assessing individual case safety reports particularly in the post- marketing setting. Challenge – In our pharmacovigilance world, this refers to the giving of the drug to the patient during the AE or treatment in question. That is, a patient is started today on, say, ampicillin orally. This is the “challenge” Dechallenge Definition – This refers to the stopping of the drug, usually after an adverse event (AE) or at the end of a planned treatment (e.g., a two-week course of ampicillin). De-challenges may be complete or partial. That is, the drug is fully stopped or decreased in dose and the AE may fully disappear or only partially decrease. The results of the dechallenge can be confusing: A positive de-challenge – This refers to the AE disappearing after the stopping of the drug. Thus, the AE (which may really be an adverse reaction – AR) of diarrhea disappeared a day after the patient stopped the ampicillin. A negative de-challenge – This refers to the AE NOT disappearing after the stopping of the drug. In our example, the diarrhea continued even after the ampicillin was stopped. Note that these can be a little confusing as a “positive” de-challenge refers to the disappearance of the problem. 26 | P a g e MEDCLINIGEN ACADEMY IF outcome after de-challenge is De-challenge is Disappeared Positive Did not disappeared Negative Not Applicable Not Applicable Unknown Unknown Re-challenge Definition – This refers to the restarting of the same drug after having stopped it, usually for an AE. Rechallenges may also be complete or partial. Thus the patient may have restarted ampicillin a week later after having stopped it. A positive rechallenge – This refers to the AE recurring after restarting the drug. To have this occur, the AE had to have previously disappeared after the de-challenge in order for it to restart. A negative rechallenge – This is the case where the AE does not recur after the drug is restarted. Note the confusion here: With a positive de-challenge the AE disappears but with a positive rechallenge the AE comes back. And vice versa. IF outcome after Re-intro is Re-challenge is Re-appeared Positive Did not reappear Negative Not Applicable Not Applicable Unknown Unknown 6. Causality Assessment Causality assessment is an assessment of relationship between a treatment drug and the occurrence of an adverse event. It is also used to evaluate and to check that the particular treatment is the cause of an observed adverse event or not and also to understand how close is the relationship between the drug the adverse event. The causality assessment system proposed by the World Health Organization Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Center (WHOUMC) and the Naranjo probability scale are the generally accepted and most widely used methods for causality assessment in clinical practice as they offer a simple methodology. There are several methods published to perform causality assessment. However, there were no internationally agreed upon standards or criteria for assessing causality in individual case safety reports. Below two methods are widely accepted ad used for assessing casuality globally. 1. WHO UMC casuality assessment. 2. Naranjo casuality assessment. 27 | P a g e MEDCLINIGEN ACADEMY WHO-UMC Causality Categories WHO-UMC Causality Categories: Certain - Event or laboratory test abnormality, with plausible time relationship to drug intake Probable/Likely - Event or laboratory test abnormality, with reasonable time relationship to drug intake Possible - Event or laboratory test abnormality, with reasonable time relationship to drug intake Unlikely - Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) Conditional/Unclassified - Event or laboratory test abnormality Unassessable/Unclassifiable - Report suggesting an adverse reaction. 28 | P a g e MEDCLINIGEN ACADEMY Assessment criteria: Below key points will aid in ease understanding of various criteria for assessing causality. 1. Temporal relationship: It is the time relationship between the drug administration (Date of therapy start date, therapy duration) and occurrence of adverse event (Event onset date/date of initial symptoms observed). 2. Abnormal Laboratory tests: There are some adverse event incidences which cannot be ruled out from the causal relation with drug based on unusual or abnormal values in the laboratory investigation. 3. Dechallenge – positive and negative 4. Rechallenge – positive and negative 5. Alternative causality: Other contributory factors for the cause of adverse event. Below are the possible contributors attributed to an AE. I. Medical conditions: Underlying concurrent medical conditions of patient (e.g., diabetes, heart diseases, autoimmune disease etc.,) or past medical history and prior or ongoing surgical procedures. II. Other medicinal product use: Concomitant medication details and past drug history. III. Social life: Alcohol use, smoking (both history & concurrent use), obesity, diet, profession etc., IV. Risk factors: Age (both pediatric and geriatric patients), hepatic and renal impairment patients etc. Identification of causal criteria based on the assessment of various factors 29 | P a g e  MEDCLINIGEN ACADEMY Adverse Drug Reaction Probability Scale (Naranjo) The Adverse Drug Reaction (ADR) Probability Scale was developed in 1991 by Naranjo and coworkers from the University of Toronto and is often referred to as the Naranjo Scale. his scale was developed to help standardize assessment of causality for all adverse drug reactions. The scale was also designed for use in controlled trials and registration studies of new medications, rather than in routine clinical practice. Nevertheless, it is simple to apply and widely used. The ADR Probability Scale consists of 10 questions that are answered as either Yes, No, or “Do not know”. Different point values (-1, 0, +1 or +2) are assigned to each answer. A simplified version of the 10 questions is provided below: The actual ADR Probability Scale form and instructions on how it is completed are provided below. Total scores range from -4 to +13; the reaction is considered definite if the score is 9 or higher, probable if 5 to 8, possible if 1 to 4, and doubtful if 0 or less. Questions Answer Score 1. Are there previous conclusive reports on this reaction? Yes +1 2. Did the adverse event occur after the suspected drug was administered? Yes +2 3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered? Yes +1 4. Did the adverse reaction reappear when the drug was Yes +2 readministered? 5. Are the alternative causes (other than the drug) that Yes -1 could have on their own caused the reaction? Do not 6. Did the reaction reappear when a placebo was given? know/not -1 done 7. Was the blood detected in the blood (or other fluids) in 0 concentrations known to be toxic? No 8. Was the reaction more severe when the dose was Do not know/ 0 increased or less severe when the dose was decreased? not done 9. Did the patient have a similar reaction to the same or +1 similar drugs in any previous exposure? Yes +1 10. Was the adverse event confirmed by any objective Yes evidence? Total Score s 6 30 | P a g e MEDCLINIGEN ACADEMY 7. ICSR A data elements of ICSR An identifiable An identifiable patient reporter An adverse A suspect drug reaction A valid safety report For regulatory reporting, the minimum data elements for a valid case The case is considered incomplete or invalid if any one of these data elements is missing The cases can be categorized into two different subsets as initial and follow up 31 | P a g e MEDCLINIGEN ACADEMY ICSR Processing Tools WHO Drug Dictionary Medical dictionary for Dictionaries regulatory activities ( MedDRA ) used in ICSR COSTART processing WHOART WHO Drug Dictionary The WHO Drug Dictionary is an international classification of medicines created by the WHO Programme for International Drug Monitoring and managed by the Uppsala Monitoring Centre. It is used by pharmaceutical companies, clinical trial organizations and drug regulatory authorities for identifying drug names in spontaneous ADR reporting (and pharmacovigilance) and in clinical trials. Created in 1968 and regularly updated, since 2005 there have been major developments in the form of a WHO Drug Dictionary Enhanced (with considerably more fields and data entries) and a WHO Herbal Dictionary, which covers traditional and herbal medicines. The WHO Drug Dictionary has previously been abbreviated as ‘WHODRL’ and may still be referenced as such. 32 | P a g e MEDCLINIGEN ACADEMY MedDRA MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry during the regulatory process, from pre-marketing to post-marketing activities, and for data entry, retrieval, evaluation, and presentation. In addition, it is the adverse event classification dictionary endorsed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. MedDRA Classification 33 | P a g e MEDCLINIGEN ACADEMY 34 | P a g e MEDCLINIGEN ACADEMY 35 | P a g e MEDCLINIGEN ACADEMY COSTART The Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) was developed by the United States Food and Drug Administration (FDA) for the coding, filing and retrieving of post-marketing adverse reaction reports. COSTART provides a method to deal with the variation in vocabulary used by those who submit adverse event reports to the FDA. Use of this dictionary allowed for stand WHOART The WHO Adverse Reactions Terminology (WHOART) is a dictionary meant to serve as a basis for rational coding of adverse reaction terms. The system is maintained by the Uppsala Monitoring Centre (UMC), the World Health Organization Collaborating Centre for International Drug Monitoring. Until 2008, when MedDRA (Medical Dictionary for Regulatory Activities) was implemented, WHO-ART was the only available terminology for coding adverse drug reactions in VigiBase. ICSR Processing Software ARISg ARGUS SAPPHIRE Advent Oracle Adverse Event Reporting System (AERS) ClinTrace PvNET repClinical Vigilanz Dynamic Monitoring System 36 | P a g e MEDCLINIGEN ACADEMY 8. ADR Reporting Systems ADR reporting systems in United Kingdom ADR reporting systems in United States 37 | P a g e MEDCLINIGEN ACADEMY ADR reporting systems in Canada ADR reporting systems in Australia 38 | P a g e MEDCLINIGEN ACADEMY Pharmacovigilance Programme of India (PvPI) Introduction: The Pharmacovigilance Programme of India (PvPI) was started by the Government of India (MoHFW) on 14th July 2010 with the All India Institute of Medical Sciences (AIIMS), New Delhi as the National Coordination Centre (NCC) for monitoring Adverse Drug Reactions (ADRs) in the country for safe-guarding Public Health. The Programme transferred to IPC as NCC in April, 2011 by a Notification issued by the MoHFW, Govt. of India. IPC-PvPI became the NCC for Materiovigilance Programme of India (MvPI) from July, 2015 IPC, NCC-PvPI became a WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes & Regulatory services from July, 2017 PvPI is under control of – CDSCO – Central Drugs Standard Control Organization Directorate of general health services 39 | P a g e MEDCLINIGEN ACADEMY PvPI objectives Goal: To ensure that the benefits of use of medicine outweighs the risks and thus safeguard the health of the Indian population. Objectives: To monitor Adverse Drug Reactions (ADRs) in Indian population To create awareness amongst health care professionals about the importance of ADR reporting in India To monitor benefit-risk profile of medicines Generate independent, evidence based recommendations on the safety of medicines Support the CDSCO for formulating safety related regulatory decisions for medicines Communicate findings with all key stakeholders Create a national center of excellence at par with global drug safety monitoring standards Aggregate Reports It is the process to periodically review the cumulative safety information & submit the findings to regulators worldwide. The exact type of reports submitted vary by country & the apporoval status of the medicine. The submission ferquency diminishes with time & when the benefit risk profile of the product becomes better understood. Important to submit aggregate reports as long as the drug in the market to know the risk benefit profile over a period of time. 40 | P a g e MEDCLINIGEN ACADEMY Pre-Market And Post Market Aggregate Reporting US IND annual reports periodic safety update report (PSUR) EU annual safety reports (ASR) periodic adverse drug experience (replaced by DSUR) reports (PADER) development safety update report periodic benefit risk evaluation (DSUR) report (PBRER) Pre- marketing Post- marketing reports reports Periodicity of Aggregate Reports UNITED STATES INDIA EUROPE JAPAN the FDA requires the DCGI periodic safety the EMA requires - every 6 months within periodic adverse drug update reports (PSUR's): periodic safety update 2 years of launch experiences reports - every 6 months for 2 reports (PSUR's): (PADER's): - annually untill the years - every 6 months for 2 ompletion of re- - Quarterly during the - annually for 2 years examination period first 3 years following years - annually for the - once in 5 years after - annual reports - thereafter as deemed following 2 years completion of re- thereafter necessary by the examination period - thereafter at 3 yearly authority intervals 41 | P a g e MEDCLINIGEN ACADEMY 10.Opportunities in PV/Drug Safety 42 | P a g e MEDCLINIGEN ACADEMY 11. FAQs 1. What is Pharmacovigilance? Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medications, biological products, herbalism and traditional medicines. 2. What is the minimum criterion required for a valid case according to WHO? a. An identifiable reporter b. An identifiable patient c. A suspect product d. An adverse drug event 3. What is an Adverse Drug Event (ADE)? Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. 4.When do you consider an event to be serious? If an event is associated with any one of the following, it is considered to be serious a. Death b. Life threatening c. Hospitalization or prolongation of hospitalization. d. Congenital anomaly e. Disability f. Medically significant 5. Name the regulatory bodies in USA, UK, Japan and India? USA: United States Food and drug administration (USFDA). UK: European Medicines Agency (EMEA). Japan: Ministry of Health, Labour and Welfare (MHLW). India: Central Drugs Standard Control Organization (CDSCO) 6.When do you consider a case to be medically confirmed? A case is considered to be medically confirmed if it contains at least one event confirmed or reported by an HCP (Health Care Professional) Note: HCP can be a physician, nurse, pharmacist, coroner or psychologist (only in Germany). 43 | P a g e MEDCLINIGEN ACADEMY 7. What do you mean by causality? Causality is the relationship between a set of factors. In Pharmacovigilance, causality is the relationship between the suspect product and the adverse drug event 8. What should a narrative consist of? A narrative should consist of precise and concise information about the source of report, patient demographics, patient’s medical history, concomitant medications, suspect product details and adverse event details in an orderly manner. 11. Explain the hierarchy in MedDRA. System Organ Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) Preferred Term (PT) Lower-Level Term (LLT) 12. What is WHO ART, WHO DD and MedDRA and the difference between them? The WHO Drug dictionary (DD), MedDRA and the WHO Adverse reactions terminology (WHO-ART). WHODD= used for drug coding MedDRA, WHO-ART = coding of events. 13. What are the types of Pharmacovigilance (PV)? Two types. 1. Active PV and 2.Passive PV Active PV: Active (or proactive) safety surveillance means that active measures are taken to detect adverse events. This is managed by active follow-up after treatment and the events may be detected by asking patients directly or screening patient records. The most comprehensive method is cohort event monitoring (CEM) Passive PV: Passive surveillance means that no active measures are taken to look for adverse effects other than the encouragement of health professionals and others to report safety concerns. Reporting is dependent on the initiative and motivation of the potential reporters. This is the most common form of pharmacovigilance. It is commonly referred to as “spontaneous” or “voluntary” reporting. 14. What is the difference between an ADE and ADR? Adverse drug event and adverse drug reaction both are adverse occurrence but if one finds the causality for adverse occurrence its adverse drug reaction and if one fails to find causality for adverse occurrence then it is referred to as adverse drug event. 15. What do you know about ICSR? The full form of ICSR is Individual Case Study Report (ICSR). It is an adverse event report for an individual patient. ICSR is based on reports/information healthcare providers and patients in member countries of the WHO Programme. 44 | P a g e MEDCLINIGEN ACADEMY 16. Do you have any idea about VigiBase? It is single largest drug safety data repository in the world. It is maintained by UMC (Uppsala Monitoring Centre) 17. What is the yellow card in pharmacovigilance? The Yellow Card Scheme is the UK system for collecting information on the suspected adverse drug reactions (ADRs) to medicines. The scheme allows the safety of the medicines and vaccines that are on the market to be monitored. In 1964, the Scheme was founded after the thalidomide disaster, and was developed by Bill Inman. 18. Difference between NDA and ANDA? NDA means New Drug Application. When the sponsor of the new drug believes that enough evidence on the drug’s safety and effectiveness has been obtained in order to meet the FDA’s requirements for the marketing approval, the sponsor submits to the FDA a new drug application. ANDA means Abbreviated New Drug Application. It contains data that, when submitted to the FDA, provides for the review and ultimate approval of the generic drug product. 19. What is EudraVigilance? The data-processing network and management system of the European Union, set up by the EMA to facilitate the electronic exchange, management and scientific assessment of individual case-safety reports on all medicinal products approved in the European Economic Area ( EEA). EudraVigilance also incorporates data analysis facilities. 20. What is Volume 9A? Volume 9A brings together general guidance on the requirements, procedures, roles and activities in the field of pharmacovigilance, for both Marketing Authorisation Holders (MAH) and Competent Authorities of medicinal products for human use; it incorporates international agreements reached within the framework of the International Conference on Harmonisation (ICH). Volume 9A is presented in four parts: Part I deals with Guidelines for Marketing Authorisation Holders; Part II deals with Guidelines for Competent Authorities and the Agency; Part III provides the Guidelines for the electronic exchange of pharmacovigilance in the EU Part IV provides Guidelines on pharmacovigilance communication. 45 | P a g e MEDCLINIGEN ACADEMY 21. Abbreviations SUSAR- Suspected Unexpected Serious Adverse Reaction SAE- Serious Adverse Event CIOMS - Council for International Organizations of Medical Sciences ADE- Adverse Drug Event SSAR- Suspected Serious Adverse Reaction ADR- Adverse Drug Reaction ICSR- Individual Case Safety Report PSUR- Periodic Safety Update Report ICH- The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use HIPAA- Health Insurance Portability and Accountability Act ESTRI- Electronic Standards for the Transfer of Regulatory Information IBD- International Birth Date 22. What do you know about E2a, E2b and E2c guidelines? E2a: E2a guidelines give standard definitions and terminology for key aspects of clinical safety reporting. It also gives guidance on mechanisms for handling expedited (rapid) reporting of adverse drug reactions in the investigational phase of drug development. E2b: E2b guidelines for the maintenance of clinical safety data management and information about the data elements for transmission of Individual Case Safety Reports. E2c: E2b guidelines for the maintenance of clinical safety data management and information about the Periodic Safety Update Reports for marketed drugs. 23. What are the types of Pharmacovigilance (PV)? Two types. 1. Active PV and 2.Passive PV Active PV: Active (or proactive) safety surveillance means that active measures are taken to detect adverse events. This is managed by active follow-up after treatment and the events may be detected by asking patients directly or screening patient records. Passive PV: Passive surveillance means that no active measures are taken to look for adverse effects other than the encouragement of health professionals and others to report safety concerns 46 | P a g e MEDCLINIGEN ACADEMY 24. What are the due dates for safety reporting? Safety reporting due dates are 7 days for IND Reporting and 15 days for NDA Reporting. 25. What is inverted Black triangle in Pharmacovigilance? A black triangle appearing after the trade name of a British medicine indicates that the medication is new to the market, or that an existing medicine (or vaccine) is being used for a new reason or by a new route of administration.The black triangle also highlights the need for surveillance of any adverse drug reaction (ADRs) that might arise from the use of a new medication. 26. What is Pharmacovigilance Programme of India (PvPI)? The Central Drugs Standard Control Organisation (CDSCO), New Delhi has initiated a nation-wide pharmacovigilance programme under the aegis of Ministry of Health & Family Welfare, Government of India. The programme is coordinated by The Indian Pharmacopoeia Commission (IPC) located at Ghaziabad. The National Coordinating Centre (NCC) is operating under the supervision of Steering Committee to recommend procedures and guidelines for regulatory interventions in India. 27. What is a signal? A ‘signal’ consists of reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. 28. Can you explain the role of a Pharmacovigilance Associate and its significance in the pharmaceutical industry? Ans: A Pharmacovigilance Associate plays a crucial role in the pharmaceutical industry by ensuring drug safety. They are responsible for monitoring, detecting, assessing and preventing adverse effects or any other drug-related problems. Their work is significant because it directly impacts patient health and safety. By meticulously tracking and analyzing data related to medication usage and side-effects, they help mitigate risks associated with pharmaceutical products. They also play a key part in regulatory compliance, as they prepare reports for health authorities and contribute to the development of guidelines and procedures within their organization.” 47 | P a g e MEDCLINIGEN ACADEMY 29. Describe your understanding of the key elements involved in the process of drug safety monitoring ? Ans; Drug safety monitoring, also known as pharmacovigilance, involves several key elements. One is the detection of adverse drug reactions (ADRs) through various sources such as clinical trials, patient reports, and healthcare professionals’ observations. Another critical aspect is the assessment and understanding of these ADRs. This includes determining their severity, frequency, and potential risk factors, which requires a thorough analysis of collected data. The third element is taking appropriate action based on the findings. This could involve updating product information, communicating risks to healthcare providers and patients, or in severe cases, withdrawing a drug from the market. Lastly, continuous monitoring and reassessment are essential to ensure the ongoing safety and efficacy of drugs.” 30. How would you handle a situation where you suspect an adverse drug reaction report is fraudulent or inaccurate? Ans: “In such a situation, I would first verify the information in the report with available data. If discrepancies persist, I’d consult with colleagues or superiors to gain their perspective. It’s crucial not to jump to conclusions but rather gather evidence. If suspicions are confirmed, it is essential to address this professionally and ethically. This could involve contacting the reporter for clarification or reporting the issue to higher management or regulatory authorities. The goal is to ensure patient safety and maintain the integrity of our pharmacovigilance system.” 31. What are the key regulations and guidelines in pharmacovigilance that you are familiar with? Example: I am familiar with several key regulations and guidelines in pharmacovigilance. The primary one is the International Council for Harmonisation (ICH) E2A, which provides clinical safety data management standards for drugs under development. Another crucial guideline is ICH E2B that focuses on electronic transmission of individual case safety reports. The European Medicines Agency’s Good Pharmacovigilance Practices (GVP) are also essential as they provide comprehensive guidance for monitoring drug safety in the EU. In the US, the Food and Drug Administration’s Code of Federal Regulations Title 21 outlines requirements for post-marketing reporting of adverse drug experiences. 48 | P a g e MEDCLINIGEN ACADEMY Understanding these regulations helps ensure compliance and effective safety monitoring throughout a product’s lifecycle.” 32. How would you handle a situation where a serious adverse event report is delayed? “In such a situation, I would first identify the cause of delay to prevent future occurrences. If it’s due to internal issues, immediate corrective measures should be implemented. Next, I’d prioritize completing and submitting the report promptly while ensuring its accuracy. It’s crucial that we communicate transparently with relevant regulatory authorities about the delay, providing an explanation and our plan to avoid similar situations in the future. Lastly, this incident would serve as a learning opportunity. I’d propose revisiting our adverse event reporting procedures and timelines, making necessary adjustments to ensure timely submissions moving forward.” 33. Knowledge based questions: Prepare yourself by freshening up your basic pharmacovigilance, regulatory body and clinical assessment knowledge ahead of your interview. Some technical questions might be:  What is day zero in pharmacovigilance?  What is the difference between an adverse event and adverse drug reaction?  What are solicited and unsolicited adverse events?  What are regulatory bodies for? 34. Competency based questions: You will also be asked competency-based questions related to your previous experiences and how you would approach various pharmacovigilance situations. For example:  Describe how you would report an adverse drug reaction?  How do you protect the privacy of patients when reporting ADR?  What are some good pharmacovigilance practises? Discuss how you have used them in the past.  Describe a time when you had to use your problem-solving skills in a clinical setting.  How do you stay up to date with the latest developments in pharmacovigilance 49 | P a g e MEDCLINIGEN ACADEMY 35. We recommend formulating your responses using the popular STAR technique:  Situation: give some context to the situation  Task: address the specific task or challenge that the situation presented  Action: what specific action did you take to resolve the task, how, and why?  Results: what were the results and benefits from this? 36. What is Signal? 37. Define Signal detection ? 38. How do you stay updated with the latest changes in pharmacovigilance regulations and guidelines? 39. What Should A Narrative Comprise? 40. Can you describe your experience with safety databases and adverse event case processing? Which specific software or tools that you know? 41. How do you assess the causality and seriousness of adverse events? What factors do you consider? 42. What are the requirements for submitting expedited reports to regulatory authorities? 43. Can you explain the process of periodic safety reporting (e.g., PSUR, DSUR) 44. Tell me something which you know about antibiotics? 45. List out Antihypertensive drugs and their categories? 46. Tell me how ACE inhibitors work ? 47. What was your Project topic/ Project Thesis? 48. Drug Schedule commonly asked ? 49. What are the different types of diabetes? 50. Name the regulatory bodies ? Ans: CDSCO: Central Drugs Standard Control Organization (India) USFDA: United States Food and Drug Administration (USA) MHRA: Medicines and Healthcare Product Regulatory Agency (UK) EMEA: European Medicines Agency (EU). MHLW: Ministry of Health, Labour and Welfare (Japan) HC: Health Canada (Canada) 51. Four parts of Volume 9A are : Ans: Part I: Guidelines for Marketing Authorisation Holders Part II: Guidelines for Competent Authorities and the Agency Part Ill: Guidelines for the electronic exchange of pharmacovigilance in the EU Part Part IV: Guidelines on pharmacovigilance communication 50 | P a g e MEDCLINIGEN ACADEMY 52. What are clinical trials? Ans: A Clinical trial is a comparison test of a medication or other medical treatment (such as medical devices), versus a placebo, other medication or devices, or the standard medical treatment for a patient’s condition. A clinical trial is an investigation in humans intended to discover or verify the effects of a drug or to identify any adverse reactions to that investigational drug with the object of ascertaining its safety and efficacy. 53. Define single and double-blinded studies. Ans: Single Blind Study: A clinical trial where the participant does not know the identity of the treatment received. Double-Blind Study: A clinical trial in which neither the patient nor the treating investigators know the identity of the treatment being administered. 54. What are the Basic Principles of Pharmacovigilance? 55. What exactly is the Pharmacovigilance Programme of India (PvPI)? Ans: The Central Drugs Standard Control Organization (CDSCO), New Delhi, has launched a national pharmacovigilance program under the auspices of the Government of India’s Ministry of Health and Family Welfare. The Indian Pharmacopoeia Commission (IPC) in Ghaziabad coordinates the initiative. The National Coordinating Centre (NCC) recommends methods and guidelines for regulatory interventions in India under the supervision of the Steering Committee. 56. When were GVP guidelines put in place? 57. What is the frequency of the DSUR? Ans: The first DSUR duration should not exceed one year. The DSUR is always filed once a year. 58. What is the frequency of PADER? Ans: PADERs were issued quarterly during the first three years. Following that, every year 59. What exactly is an orphan drug? Ans: A drug (or biological product) used to prevent, diagnose, or cure a Rare Disease, or to diagnose a life-threatening or persistently debilitating disease. 60. What Is a Dead Leg? Ans: A dead leg is a section of piping where liquid can get stagnant and not be transferred during flushing. 51 | P a g e MEDCLINIGEN ACADEMY 61. What exactly is SAS? Ans: SAS stands for Statistical Analysis System, which is a collection of software packages. 62. What exactly is polypharmacy? Ans: Concurrent use of many drugs, sometimes prescribed by separate practitioners. 63. What exactly is VigiBase? Ans: The WHO Global ICSR Database’s name. 64. What exactly is VigiFlow? Ans: The UMC developed and maintains VigiFlow, a comprehensive ICSR management system. It can be utilized as the national database for nations participating in the WHO Programme since it includes capabilities for report analysis and makes transmitting reports to VigiBase easier. 65. What are the Roles in Pharmacovigilance? Ans: Drug Safety Associate / Drug Safety Scientist Pharmacovigilance expert o Drug Safety Physician Medical reviewer Pharmacovigilance Executive Pharmacovigilance associate Pharmacovigilance – Data Analyst Pharmacovigilance Scientist Medical Safety Expert 65 HR round interview question in Pharmacovigilance? Ans: Tell me about your family Where from you, place name, Working hours Shifting Off day Facilities Salary discussion Documents 52 | P a g e MEDCLINIGEN ACADEMY 66. Name some anticancer drugs and what is antibiotic resistance ? 67. Define LD50 and ED50 ? 68. What are the due dates for Safety reporting ? 69. What is inverted black triangle in pharmacovigilance ? 70. What are augmented reactions and give one example ? 71. What are Bizarre reactions and give one example ? 72. What is seriousness criteria based on intensity ? 73. Define Triage ? 74. What is expectedness ? 75. What is unexpectedness ? 76. What are Unsolicited reports ? 77. Define Spontaneous report ? 78. Define Literature reports ? 79. Who are eligible to report? 80. What are reporting forms to US FDA ? 81. Drug dictionaries used in pharmacovigilance ? 82. Labelling of Investigational new drug ? 83. Signal management process ? 84. What is signal validation ? 85. What is auditing and inspection ? 86. What is suspect drug ? 87. What is treatment drug ? 88. What is concominant drug ? 89. Define medication error ? 90. What is Drug misuse ? 91. What is Benefit Risk Analysis? 92. What is Absolute Risk ? 93. What is CCDS ? 94. Define Data Lock Point ? 95. What is False Signal ? 96. What is Post authorization safety study ? 97. PTC Documents for MEDRA ? 98. Define IB, EUSMPC, PIL, and USPI ? 99. What are reference safety information documents ? 100. Define IME, EDC, eCRF, CSR ? 53 | P a g e MEDCLINIGEN ACADEMY THANK YOU 54 | P a g e