BP805ET · PHARMACOVIGILANCE

✔ Correct — B: WHO (2002) defines Pharmacovigilance (PV) as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem." Scope extended beyond ADRs to: medication errors, lack of efficacy, product quality defects, misuse / abuse, off-label use, counterfeits, interactions, therapeutic failure, environmental exposure, overdose. Word origin: pharmakon (drug) + vigilare (to keep watch). Goals: patient safety, public health, rational drug use, risk-benefit evaluation throughout product lifecycle.

✔ Correct — A: Thalidomide (Contergan, marketed 1957) prescribed for pregnancy nausea caused severe birth defects — phocomelia (seal-limb), heart / GI / renal / auditory anomalies in ~ 10,000 infants. W. Lenz + W.G. McBride linked it 1961. Led to: stringent pre-market safety testing, teratogenicity studies (ICH S5), WHO International Drug Monitoring Programme (1968), UK Yellow Card (1964), US Kefauver-Harris Amendment (1962) requiring proof of efficacy + safety. Dr. Frances Kelsey (FDA) blocked US approval. Thalidomide now approved for leprosy (ENL) + multiple myeloma under strict REMS.

✔ Correct — C: WHO PIDM launched 1968 post-thalidomide with 10 founding countries. Uppsala Monitoring Centre (UMC) in Sweden became WHO Collaborating Centre 1978 (managed by Swedish Medical Products Agency). Maintains VigiBase — world's largest ICSR database (> 35 million reports from 170+ countries). Member countries submit national reports. India joined 1998. PIDM + UMC together form global PV infrastructure. WHO-ART (Adverse Reaction Terminology) replaced by MedDRA. Signal detection by disproportionality analysis (PRR, ROR, BCPNN, GPS).

✔ Correct — D: PV objectives (WHO): (1) improve patient care + safety; (2) improve public health + safety; (3) assess benefit-harm-risk-effectiveness of medicines; (4) promote understanding + education in PV + effective communication to public; (5) encourage safe + rational drug use. Identifies previously unrecognised risks (Type B), changes in frequency, at-risk populations (elderly, paediatric, hepatic/renal impairment), interactions, off-label use issues. Supports regulatory decisions (label updates, restrictions, withdrawal).

✔ Correct — B: WHO 1972: ADR = "a response to a drug which is noxious, unintended and occurs at doses normally used in man for prophylaxis, diagnosis or therapy." Excludes: overdose (intentional / accidental), abuse / misuse, medication errors, therapeutic failure. Contrast Adverse Event (AE) = any untoward medical occurrence in a patient administered a drug, whether or not causally related. All ADRs are AEs; not all AEs are ADRs. Side effect = any pharmacological effect other than the desired one (positive or negative).

✔ Correct — A: Rawlins + Thompson 1977 ABCDE classification: Type A (Augmented) — exaggerated pharmacological action, dose-dependent, predictable (bleeding with anticoagulants, bradycardia with β-blockers, sedation with BZD, hypoglycaemia with sulfonylurea); common; low mortality; managed by dose reduction. Type B (Bizarre) — idiosyncratic, not dose-related (anaphylaxis, SJS, agranulocytosis); rare; high mortality. Type C (Chronic, dose + time related — cushing with steroid, analgesic nephropathy). Type D (Delayed — teratogenicity, cancer). Type E (End-of-use withdrawal). Extended F (Failure), G (Genetic).

✔ Correct — C: SJS + TEN = severe cutaneous adverse reactions (SCARs) — Type B idiosyncratic, immune-mediated. Classical triggers: anti-epileptics (carbamazepine, lamotrigine, phenytoin), sulfonamides (cotrimoxazole), allopurinol, NSAIDs (oxicams), nevirapine. Genetic predisposition: HLA-B*15:02 (CBZ-SJS in Asians; mandatory screening), HLA-B*58:01 (allopurinol SCAR). SJS ≤ 10 % BSA, TEN ≥ 30 %, overlap 10-30 %. Mortality SJS 5-10 %, TEN 30-50 %. SCORTEN prognostic score. Management: ICU / burn care, supportive, withdraw culprit, IVIG / cyclosporine / etanercept.

✔ Correct — D: DoTS framework (Aronson + Ferner 2003, BMJ) complements A-G classification. Dose relatedness: toxic effect (above therapeutic), collateral (normal dose), hypersusceptibility (below therapeutic). Time course: time-independent (any time), time-dependent (rapid — acute; early — withdraw; intermediate — tolerance; late — cumulative; delayed — teratogenic / cancer). Susceptibility: age, sex, physiology (pregnancy, organ function), exogenous (interactions), endogenous (genetic — pharmacogenomics). Provides systematic clinical framework — better than letters.

✔ Correct — A: ICH E2A definition — serious AE (SAE) / serious ADR: outcome is death, life-threatening, requires or prolongs hospitalisation, results in persistent / significant disability or incapacity, causes congenital anomaly / birth defect, or is medically significant (may jeopardise subject, require intervention). Seriousness ≠ severity (mild / moderate / severe). Serious ADRs trigger expedited 15-day reporting to regulators (21 CFR 314.80 / EU). Non-serious ADRs aggregated in PSUR / PBRER.

✔ Correct — B: Hartwig + Siegel severity scale (1992) grades ADRs into Level 1-7: mild (no change, level 1-2), moderate (change in therapy / additional monitoring, 3-4), severe (ICU admission, antidote, permanent disability, death, 5-7). Distinct from Naranjo (causality) + Schumock-Thornton (preventability). CTCAE v5.0 = NCI grading for oncology AEs: Grade 1 mild, 2 moderate, 3 severe, 4 life-threatening, 5 death. Grading informs treatment decisions + regulatory reporting.

✔ Correct — C: Predictable (Type A / Augmented) ADRs follow pharmacological action. Examples: bleeding with anticoagulants (warfarin, DOACs, heparin), hypoglycaemia with insulin / sulfonylureas, bradycardia with β-blockers, sedation with CNS depressants (BZD, opioids, antihistamines), orthostatic hypotension with α-blockers, bronchospasm with β-blockers (β2), dry cough with ACEi (bradykinin), hyperkalaemia with K-sparing diuretics / ACEi, tachycardia with salbutamol. Dose-dependent → managed by dose reduction / TDM / careful monitoring.

✔ Correct — D: Idiosyncratic reactions (Type B) are genetically determined or immune-mediated abnormal responses occurring at normal therapeutic doses. Examples: anaphylaxis (IgE), SJS / TEN (T-cell HLA-restricted), DRESS, agranulocytosis (clozapine, carbimazole, ticlopidine), aplastic anaemia (chloramphenicol), hepatotoxicity (flucloxacillin, isoniazid, pyrazinamide), haemolysis (primaquine / sulfonamide in G6PD deficiency), malignant hyperthermia (RyR1 mutation + volatile anaesthetic / succinylcholine), porphyria exacerbation. Difficult to detect in pre-marketing trials due to rarity.

✔ Correct — A: Type C (Chronic, Continuous, dose + time-related): effects from prolonged exposure. Examples: Cushing syndrome + osteoporosis + adrenal suppression + skin atrophy with chronic corticosteroids; analgesic nephropathy (chronic NSAIDs / phenacetin); tardive dyskinesia (antipsychotics); aluminium encephalopathy (long-term antacid); digital osteoporosis / tooth discolouration with tetracyclines. Type D (Delayed — teratogenesis: thalidomide, warfarin, ACE-i, valproate; carcinogenesis: DES vaginal clear-cell carcinoma). Type E (End-of-use withdrawal — rebound tachycardia, opioid withdrawal, steroid adrenal crisis). Type F (Failure of therapy: ineffective OC with enzyme inducers). Type G (Genetic).

✔ Correct — B: Teratogens (cross placenta, affect fetus): thalidomide (phocomelia), warfarin (nasal hypoplasia, stippled epiphyses, CNS), ACE-inhibitors + ARBs (2nd + 3rd trimester renal / oligohydramnios), valproate (NTD, heart, orofacial), carbamazepine + phenytoin (NTD, fetal hydantoin syndrome), lithium (Ebstein anomaly), isotretinoin (craniofacial, CNS, cardiac), methotrexate (multiple), tetracycline (teeth discolouration + bone), aminoglycosides (ototoxicity), androgens (virilisation), DES (clear-cell vaginal Ca decades later), chemotherapy. Most sensitive period: week 3-8 (organogenesis). FDA categories A/B/C/D/X (replaced 2015 by PLLR narrative labelling).

✔ Correct — C: Pharmacogenetic ADRs (Type G) result from genetic variation in drug targets / metabolising enzymes. Examples: G6PD deficiency → haemolysis with primaquine, dapsone, nitrofurantoin, sulfonamides, rasburicase; TPMT deficiency → azathioprine / mercaptopurine myelotoxicity; CYP2D6 poor metabolisers → codeine no effect / ultra-rapid → morphine toxicity; CYP2C9 + VKORC1 → warfarin sensitivity; CYP2C19 → clopidogrel resistance (↓ antiplatelet); HLA-B*57:01 → abacavir hypersensitivity; HLA-B*15:02 → CBZ-SJS (Asians); DPD deficiency → 5-FU toxicity; NAT2 slow → INH hepatitis / peripheral neuropathy; CPIC / CPNDS guidelines.

✔ Correct — A: Amiodarone inhibits CYP2C9 + CYP3A4 + P-glycoprotein → ↑ warfarin levels → major bleeding. Monitor INR, reduce warfarin 25-50 %. Other classic DDIs: MAO-inhibitor + tyramine / pethidine (hypertensive / serotonin crisis); SSRI + triptan → serotonin syndrome; ACEi + K-sparing diuretic → hyperkalaemia; digoxin + verapamil → ↑ digoxin; statin + fibrate / macrolide / CCB → rhabdomyolysis; oral contraceptive + rifampicin → failure; clopidogrel + PPI (omeprazole) → ↓ activation; metformin + contrast → lactic acidosis / AKI; linezolid + SSRI → serotonin syndrome; 3A4 inhibitors (grapefruit, clarithromycin, ketoconazole) + many substrates.

✔ Correct — D: Serotonin syndrome (Sternbach / Hunter criteria) = triad: (1) mental (agitation, confusion, coma); (2) autonomic (hyperthermia > 38.5 °C, tachycardia, hypertension, diaphoresis, mydriasis, diarrhoea); (3) neuromuscular (clonus — especially lower limbs, hyperreflexia, rigidity, tremor). Causes: SSRI + MAOI combination, SSRI + triptan / linezolid / tramadol / ondansetron / MDMA, TCA + MAOI. Management: stop serotonergic agent, supportive cooling, benzodiazepines, cyproheptadine (5-HT2A antagonist). Differential: neuroleptic malignant syndrome (NMS) slower onset, "lead-pipe" rigidity, dopamine antagonists; malignant hyperthermia after volatile anaesthetic.

✔ Correct — B: Side effect (WHO) = any unintended effect of a pharmaceutical product at normal doses related to its pharmacological properties — can be beneficial (aspirin for cardiovascular prevention in low dose, dutasteride for hair growth) or harmful. Broader than ADR (which is specifically noxious). Used in lay language interchangeably with ADR. Adverse Drug Reaction vs Adverse Drug Event (AE) vs Side effect: ADR ⊂ AE; side effects include both beneficial + harmful + neutral unintended effects.

✔ Correct — C: Rofecoxib (Vioxx, Merck 1999) = COX-2 selective NSAID for osteoarthritis + pain. Withdrawn September 2004 after APPROVe trial showed ~ 2-fold increased MI + stroke risk beyond 18 months. Mechanism: selective COX-2 inhibition imbalances prostacyclin (PGI2, vasodilator / antiplatelet) vs thromboxane A2 (TXA2, vasoconstrictor / platelet aggregator) → prothrombotic. Class-wide signal; valdecoxib (Bextra) also withdrawn 2005. Celecoxib survived with warnings. Landmark case for PV + PMS importance. Litigation > $ 4.85 billion.

✔ Correct — A: Inverted black triangle (▼) on UK (MHRA) + EU (EMA) product information indicates additional monitoring (since 2013 per Regulation 1027/2012). Applied for: first 2 years post-authorisation, biosimilars, conditional approvals, approvals under exceptional circumstances, drugs requiring PASS / RMP studies. HCPs + patients encouraged to report all suspected ADRs (serious or not) via Yellow Card / eAdrReport. Symbol retained for ≥ 5 years. Website: www.mhra.gov.uk/yellowcard. EU analog: EudraVigilance.

✔ Correct — B: SRS = voluntary reporting by healthcare professionals, patients, marketing authorisation holders (MAH) of suspected ADRs via national forms (Yellow Card UK, MedWatch US, VigiFlow India, EudraVigilance EU). Most common + cost-effective PV method. Covers all marketed drugs + all patient populations + entire product life. Limitations: underreporting (5-10 % of actual ADRs), selection bias (serious / new drugs over-reported), missing numerator (no denominator — can't compute incidence), signals only (not causation). WHO PIDM + VigiBase aggregate global reports.

✔ Correct — D: CEM = prospective observational method: enrol defined cohort (typically 10,000-30,000) of patients starting new drug; record all clinical events (not just suspected ADRs) during follow-up; compute incidence rates. WHO uses CEM for new antimalarials (artemisinin combinations), antiretrovirals, new TB drugs (bedaquiline). Advantages: captures rare ADRs, establishes incidence (denominator), identifies at-risk populations. Limitations: expensive, lengthy, requires dedicated team. PEM (Prescription Event Monitoring) UK variant: Drug Safety Research Unit (DSRU) Southampton pioneered since 1980.

✔ Correct — A: PEM (Drug Safety Research Unit DSRU Southampton, UK, since 1980): identifies 10,000+ patients via NHS Prescription Pricing Authority dispensing records; sends "green forms" to GP at 3-12 mo asking for all events + outcome + cause. Advantages: large, near-real-world, non-interventional, detects rare ADRs. Modern evolution: M-PEM (Modified PEM with electronic health records), SEM (Specialist Cohort Event Monitoring). CPRD + THIN + QResearch = UK database alternatives. India IPSN (Pharmacoepidemiology Surveillance Network) emerging.

✔ Correct — C: Case-control used in PV to confirm/deny drug-ADR signal by comparing exposure prevalence in cases (have ADR) + controls (don't). Classic: COCs + VTE (Jick 1966), DES + vaginal clear cell ca, aspirin + Reye's syndrome, HRT + breast cancer, rosiglitazone + MI (Nissen). Advantages: rare outcomes, retrospective, cheaper than cohort. Gives odds ratio (OR). Limitations: recall bias, selection bias, cannot establish causality alone. Nested case-control within a cohort combines strengths.

✔ Correct — B: Phase IV = post-marketing surveillance after drug approval. Objectives: detect rare ADRs (1 in 10,000+), long-term effects, drug interactions, real-world effectiveness, special populations (elderly, paediatric, hepatic / renal, pregnancy), comparative effectiveness. Methods: spontaneous reports, PSUR/PBRER, PASS (post-authorisation safety study), registries, pharmacoepidemiology, big data analytics. Phase IV studies can be required as regulatory conditions. India: NDCT Rules 2019 mandate PMS for 4 years for new drugs.

✔ Correct — A: Passive PV = relies on voluntary reporting without active pursuit — spontaneous reports, case reports, case series, published literature. Low cost, broad coverage, but underreported. Active PV = deliberately solicits safety data via: CEM / PEM, sentinel sites (FDA Sentinel Initiative, EU DARWIN), drug registries (pregnancy registries — exposure databases for teratogens; disease registries — rheumatoid, MS, IBD), electronic health records (EHR) data mining, chart review, record linkage. Hybrid approaches: stimulated reporting, targeted spontaneous reporting, eHealth.

✔ Correct — D: FDA Sentinel Initiative (launched 2008, full operation 2014 as Sentinel System) = active post-market safety surveillance using distributed, de-identified electronic health data from claims + EHR of ~ 300+ million US residents. Partners: Medicare, Medicaid, insurers, integrated delivery systems. Runs standardised queries for signal verification, safety assessment, signal-refinement analyses. Saves on PMR (post-marketing requirement) studies. EU DARWIN (Data Analysis + Real-World Interrogation Network) is EMA analog. CPRD (UK Clinical Practice Research Datalink) separate database.

✔ Correct — B: Targeted Spontaneous Reporting (TSR) focuses ADR collection on defined priority drugs or events (e.g. new ARVs, anti-TB in MDR / DR-TB programmes, maternal-health drugs, biologicals, biosimilars, novel therapies). Advocated by WHO for resource-limited settings; more efficient than passive SRS. India: NTEP + NACP integrate TSR. Stimulated reporting = TSR + reminders, training, feedback loops. Complements SRS for high-priority monitoring.

✔ Correct — C: Underreporting (Hazell + Shakir meta-analysis 2006): median reporting rate ~ 6 % of all ADRs; ~ 90-95 % underreported. Higher for serious (~ 80 % reported), much lower for non-serious / known ADRs. Reasons: complacency (known ADRs not reported), fear of litigation, ignorance (what/how to report), lethargy, diffidence, indifference, ambition to publish separately. Remedies: HCP education, simple forms (electronic, mobile app), positive feedback, mandatory reporting (for serious events), integrating into EMR workflow. India PvPI < 0.01 ICSR per 1000 prescriptions (vs UK 0.5, US 0.3).

✔ Correct — A: VigiFlow = WHO-UMC web-based ICSR management system. India PvPI ADR Monitoring Centres (AMCs) enter reports into VigiFlow → National Coordination Centre (IPC Ghaziabad) → VigiBase. Mobile app: ADR PvPI (available Android / iOS) for patients + HCP reporting in English + Hindi. Tollfree helpline 1800-180-3024. Other forms: Form CDSCO (paper) + MedWatch 3500 (US FDA) + Yellow Card (UK MHRA) + EudraVigilance EV-WEB (EU). WHO-UMC also offers VigiLyze for signal detection.

✔ Correct — D: Disproportionality analyses flag drug-event pairs occurring more than expected based on background reporting rate. Frequentist: PRR (Proportional Reporting Ratio; MHRA, > 2, χ² > 4, n ≥ 3 threshold), ROR (Reporting Odds Ratio; EudraVigilance). Bayesian: BCPNN (Bayesian Confidence Propagation Neural Network; UMC IC value > 0 + IC₀₂₅ > 0), GPS / Multi-item GPS (MGPS) / EBGM / EB05 (FDA). 2×2 table: cases of drug-event / drug-other / other-event / other-other. Automated screening in VigiBase, FAERS, EudraVigilance. Signals confirmed by clinical review + literature + additional studies.

✔ Correct — B: WHO-UMC 2002: signal = "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 one report is required...depending on seriousness of event + quality of information." Signal detection → validation → prioritisation → assessment → recommendation → action. Signals may lead to: label update, restrictions (age, dose, indication), DHPC (Dear HCP Letter), market withdrawal, risk-management plan. Signal management is iterative + evidence-based.

✔ Correct — A: PASS (Post-Authorisation Safety Study) = any study relating to an authorised medicinal product conducted with the aim of identifying, characterising, or quantifying a safety hazard or measuring effectiveness of risk-minimisation. May be imposed (regulatory obligation, condition of MA) or voluntary. EU PAS register. Designs: cohort, case-control, cross-sectional, drug utilisation, registries, RCT. ENCePP (European Network of Centres for Pharmacoepidemiology + Pharmacovigilance) hosts guidelines + checklist. PAES = Post-Authorisation Efficacy Study (effectiveness).

✔ Correct — C: NCC MERP definition: medication error = "any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient or consumer." Stages: prescribing (wrong drug, dose, frequency, LASA), dispensing (wrong drug, label), administration (wrong patient, route, time, 5 rights), monitoring (missed). Categories A-I (A no error capacity, B no reach, C reached no harm, D monitoring needed, E temporary harm + intervention, F + hospitalisation, G permanent, H near-death, I death). Distinct from ADR (which is unintended even with correct use). Medication errors are preventable; ADRs largely not.

✔ Correct — D: CIOMS Form I (Council for International Organisations of Medical Sciences) = standardised international format for reporting single ADR cases between sponsors + regulators. Widely used for expedited 15-day serious unexpected ADR submission from industry to authorities. Contains: patient info, reaction / event, suspect drug(s), reporter. CIOMS II Form = line listing for multiple cases in PSUR. ICH E2B (R3) XML format superseded paper forms. CIOMS also issues white papers + recommendations (CIOMS VI CT safety, CIOMS VIII signal detection).

✔ Correct — A: DUR / DUE (Drug Use Evaluation) = structured, ongoing, authorised review of prescribing + dispensing + patient use of medications to ensure optimal outcomes. Types: prospective (before dispensing — DUR alerts in pharmacy IT for interactions, duplicates, dose issues, allergies), concurrent (during therapy), retrospective (audit after use). WHO DUR indicators: avg drugs / prescription, % antibiotics, % injections, % generic, % from EML. Feedback to prescribers + educational interventions reduce inappropriate use. Complements PV by identifying patterns leading to ADRs.

✔ Correct — C: MAH (Marketing Authorisation Holder) = company / entity responsible for placing medicinal product on market. Legal responsibility for product quality + safety + efficacy throughout life cycle. PV obligations: maintain PV system master file (PSMF), appoint Qualified Person for Pharmacovigilance (QPPV in EU, contact person US), submit ICSRs, PSUR / PBRER, RMP, respond to regulator queries, conduct PASS + risk-minimisation, label updates, DHPC communication, product withdrawal, renewals. In India: Responsible Person PV (RPP). Small companies may outsource to PV CRO.

✔ Correct — B: QPPV = Qualified Person for Pharmacovigilance, EU-wide role mandated under Directive 2010/84/EU. Resident of EU / EEA, single-point responsibility for PV system of MAH; 24/7 contact for regulators. Duties: overseeing PV system (PSMF), ensuring submissions (ICSR, PSUR, RMP), signal management, responding to inspections, PASS oversight. Deputy QPPV common. Reports to senior management. ICH E2A + GVP modules frame responsibilities. Non-EU markets have analogous roles (India RPP; US contact person; UK QPPV post-Brexit).

✔ Correct — A: PSUR (Periodic Safety Update Report, ICH E2C R2 since 2012 renamed PBRER — Periodic Benefit-Risk Evaluation Report). Submitted by MAH to regulators. Classical intervals: 6-monthly first 2 y, annually 3-4 y, every 3 y thereafter; EU EURD list sets harmonised data lock points + frequencies for products. Content: worldwide drug exposure, cumulative + interval safety data, signals, PASS progress, benefit evaluation, overall benefit-risk analysis, recommended actions. DSUR (Development Safety Update Report, ICH E2F) = analogous for drugs still in clinical development.

✔ Correct — D: Pharmacovigilance safety monitoring governed by ICH E2A (definitions + standards), E2B (ICSR data elements + XML format), E2C (PSUR → PBRER), E2D (post-approval expedited reporting definitions), E2E (pharmacovigilance planning), E2F (DSUR). EU GVP (Good Pharmacovigilance Practices) modules I-XVI + product/population specific chapters (EMA 2012-). ISO 9001 = general QMS (pharma industry applies), ISO 13485 = medical devices, ISO 22000 = food. CIOMS working groups publish white papers. Not covered by ISO alone; ICH + GVP are PV-specific.

✔ Correct — B: WHO + ICH E2B minimum ICSR data (4 elements): (1) identifiable patient (age, sex, initials, unique ID), (2) identifiable reporter (HCP, consumer with verifiable contact), (3) suspect drug (name, batch if possible), (4) suspected adverse reaction (description). Incomplete reports still captured, follow-up pursued. Full ICSR adds: medical history, concomitant drugs, indication, therapy dates, dose, route, outcome (recovered, continuing, fatal, unknown), de-challenge / re-challenge, causality assessment, narrative. E2B R3 XML has 380+ fields. Confidentiality preserved (no patient identifier transmitted).

✔ Correct — A: De-challenge = stopping suspect drug; improvement supports causality (positive de-challenge). Re-challenge = re-exposure; recurrence strongly supports causality (positive re-challenge — highest probability). Positive DC + positive RC = definite ADR per Naranjo (scores +1 each). Ethical considerations: re-challenge only when necessary, not for serious / life-threatening reactions. Absent / negative response weakens causality. Spontaneous resolution without de-challenge is "no de-challenge applied." Key field in CIOMS Form I + E2B.

✔ Correct — C: Naranjo score: Definite ≥ 9, Probable 5-8, Possible 1-4, Doubtful ≤ 0. Ten-item yes/no questionnaire (+/− / don't know points): previous reports, temporal sequence, dechallenge improvement, rechallenge recurrence, alternative cause, placebo response, toxic levels, dose-response, previous history, objective evidence. Simple, widely used. Alternatives: WHO-UMC (Certain / Probable / Possible / Unlikely / Conditional / Unassessable — based on narrative), Liverpool ADR Causality Assessment Tool (LCAT — more rigorous). Experts + algorithm + Bayesian + global introspection complement.

✔ Correct — A: WHO-UMC Certain = clinical event with plausible time sequence after drug intake; cannot be explained by disease / other drugs; response to withdrawal clinically plausible (positive de-challenge); event pharmacologically / phenomenologically definitive; rechallenge if done is positive. Probable / Likely = similar but alternative cause less clearly ruled out. Possible = temporal but could be other cause. Unlikely = time-course makes causality improbable. Conditional / Unclassified = needs more data. Unassessable / Unclassifiable = cannot be judged due to missing info.

✔ Correct — B: SUSAR from clinical trials reported by sponsor: fatal / life-threatening within 7 days (written follow-up 8 days later); all other SUSARs within 15 days. Post-marketing serious unexpected reactions: 15 calendar days (21 CFR 314.80 / EU equivalent). Non-serious post-marketing in aggregate (PSUR). Reports to national authorities + IRB/IEC + other investigators. SUSAR = Suspected (causality suspected) + Unexpected (not in Investigator's Brochure / SmPC) + Serious + Adverse Reaction. Annual DSUR (Development Safety Update Report, ICH E2F) aggregates CT safety.

✔ Correct — D: MedDRA 5-tier hierarchy (ICH, managed by MSSO): System Organ Class (SOC, 27 — Gastrointestinal, Cardiac, Nervous system, etc.) → High-Level Group Term (HLGT) → High-Level Term (HLT) → Preferred Term (PT — standard coded term for ICSR, e.g. Nausea, Myocardial Infarction) → Lowest-Level Term (LLT — synonyms + colloquial). Updated semi-annually March + September. SMQ (Standardised MedDRA Queries) = pre-validated groupings for safety topics (e.g. Hypersensitivity, QT prolongation, Hepatic disorders). Available in 18 languages. Maintains cross-walk to WHO-ART (legacy).

✔ Correct — A: SMQ (Standardised MedDRA Query) = validated + maintained groupings of MedDRA PTs that relate to a defined medical condition / safety topic, designed to facilitate retrieval + analysis in safety databases. ~ 100+ SMQs available. Examples: Hypersensitivity, Hepatic disorders, Renal failure, QT prolongation, Torsade de pointes / QT prolongation, Rhabdomyolysis / myopathy, Acute pancreatitis, Acute renal failure, Suicide / self-injury, Drug abuse + dependence, Pregnancy + fetal disorders, Haemolysis, Neuroleptic malignant syndrome. Two tiers: narrow (high specificity) + broad (high sensitivity). Used in signal detection, PSUR review, drug-safety analyses.

✔ Correct — C: Causality scales: (1) Naranjo (1981, 10-item yes/no, score 0-13 — Definite ≥ 9, Probable 5-8, Possible 1-4, Doubtful ≤ 0); (2) WHO-UMC (narrative-based — Certain / Probable / Likely / Possible / Unlikely / Conditional / Unassessable); (3) Liverpool ADR Causality Assessment Tool (LCAT 2011 — decision-tree, reproducible); (4) Karch + Lasagna; (5) Kramer + Hutchinson; (6) Jones; (7) Bayesian Adverse Reaction Diagnostic Instrument (BARDI); (8) Global Introspection. Other scales in PV: Hartwig-Siegel (severity), Schumock-Thornton (preventability), CTCAE (oncology grade 1-5), APACHE (ICU severity, unrelated).

✔ Correct — B: Schumock-Thornton (1992) criteria = 7-question algorithm classifying ADR preventability as definitely preventable, probably preventable, or not preventable. Questions: drug inappropriate for clinical condition / patient, dose / route / frequency inappropriate, required therapeutic drug monitoring / laboratory not performed, previous allergy / ADR history for drug, drug interaction known, toxic serum drug level, non-adherence. Identifies system / process failures → CAPA target. Complements causality (Naranjo) + severity (Hartwig) for complete ADR characterisation.

✔ Correct — C: Hy's Law (Hy Zimmerman observation, FDA 2009 guidance): drug-induced hepatocellular injury with: ALT / AST > 3× ULN + total bilirubin > 2× ULN + no other cause (e.g. biliary obstruction, viral hepatitis) → ~ 10 % mortality / liver transplant risk. Signals serious DILI (drug-induced liver injury) potential in clinical trials → regulatory concern (troglitazone, bromfenac, trovafloxacin withdrawals). R value = (ALT/ULN) / (ALP/ULN): R > 5 hepatocellular, < 2 cholestatic, 2-5 mixed. RUCAM (Roussel Uclaf Causality Assessment Method) specific for DILI. Paracetamol, INH, methotrexate, amiodarone, halothane classic hepatotoxins.

✔ Correct — A: QT-prolonging drugs → TdP (torsade de pointes) risk → polymorphic VT → sudden cardiac death. Block hERG K+ channel (IKr). Classes: Class IA antiarrhythmics (quinidine, procainamide), Class III (amiodarone, sotalol, dofetilide, ibutilide), macrolides (erythromycin, clarithromycin, azithromycin less), fluoroquinolones (moxifloxacin > ciprofloxacin), azole antifungals (fluconazole, voriconazole), methadone, tricyclic antidepressants, SSRIs (citalopram, escitalopram high), antipsychotics (haloperidol, ziprasidone, quetiapine, thioridazine), ondansetron, domperidone, chloroquine / hydroxychloroquine. ICH E14 mandates thorough QT study (TQT). CredibleMeds.org maintains list.

✔ Correct — B: QTc (rate-corrected QT, Bazett / Fridericia formula): normal < 440 ms men, < 460 ms women. Prolongation > 450 ms M / 470 ms F (borderline). Clinically significant: > 500 ms or > 60 ms increase from baseline — associated with TdP risk → stop suspect drug + correct electrolytes (K, Mg, Ca) + refer cardiology. Congenital Long QT (KCNH2, KCNQ1) at baseline risk. Risk factors: female, elderly, hypokalaemia, hypomagnesaemia, bradycardia, HF, CYP3A4 inhibitors (↑ QT drug levels). ICH E14 TQT study standard + C-QT modelling in early CT.

✔ Correct — D: Global introspection = clinician's overall judgement of drug-event causality based on clinical experience, pattern recognition, alternative explanations. Pros: flexibility, integrates nuances; Cons: subjectivity, variability, non-reproducibility. Contrast with algorithm-based (Naranjo, WHO-UMC, Liverpool — structured, reproducible) + Bayesian (quantitative probability). Regulators prefer algorithmic for standardisation; hepatology uses RUCAM. Multi-reviewer consensus improves reliability. ICH M10 is bioanalytical validation; ICH E2A-F govern PV causality framework.

✔ Correct — A: WHO-UMC categories: Certain, Probable / Likely, Possible, Unlikely, Conditional / Unclassified, Unassessable / Unclassifiable. "Definite overdose" not a causality category — overdose reactions are excluded from ADR per WHO definition. Certain requires positive de-challenge + re-challenge + no alternative + objective evidence. Probable similar but alternative less fully excluded. Possible = temporal; alternative plausible. Unlikely = time-course makes relationship improbable. Conditional = missing data. Unassessable = information insufficient.

✔ Correct — C: ADR expected / listed vs unexpected judged against current product information — SmPC (Summary of Product Characteristics, EU), USPI (US Prescribing Information), label / package insert (India, other markets). In clinical trials, Investigator Brochure (IB) is reference document. Unexpected = not previously observed, or a known effect at higher frequency / severity than listed. Expedited reporting (15-day) applies to serious + unexpected reactions. Listed serious reactions reported in PSUR. Reference Safety Information (RSI) specified in IB for sponsor's expectedness assessment.

✔ Correct — B: Latency (time-to-onset) = interval between first drug exposure and ADR onset. Critical causality clue. Typical patterns: Type I allergy — minutes (anaphylaxis), Type II cytotoxic — days-weeks, Type III immune complex — 7-21 days (serum sickness), Type IV delayed — days-weeks (DRESS), SJS/TEN — 4-28 days after start, hepatotoxicity variable (acute — days-weeks, chronic — months), teratogenicity — organogenesis (wk 3-8), tardive dyskinesia — years. Biphasic anaphylaxis can occur 8-72 h after initial. Cumulative toxicity (aminoglycoside oto, anthracycline cardio) dose-total related. Time-to-onset guides temporal plausibility assessment.

✔ Correct — A: NNH = 1 / absolute risk increase (ARI). Example: if drug causes 2 extra MIs per 100 patients/yr, NNH = 50. Contrast NNT (Number Needed to Treat) = 1 / ARR. Complementary: NNT-to-NNH ratio helps weigh benefit / harm. Confidence intervals important. Rosiglitazone 2007 meta-analysis (Nissen): excess MI NNH ~ 200 → withdrawal. Class effects (NSAIDs CV risk, statins diabetes). Paediatric SSRIs + suicidal behaviour NNH ~ 100. Used in drug-safety communication, DHPC, risk-benefit framing.

✔ Correct — D: Structured benefit-risk assessment frameworks: BRAT (Benefit-Risk Action Team, CIRS), PrOACT-URL (Problem, Objectives, Alternatives, Consequences, Trade-offs + Uncertainty, Risk attitude, Linked decisions; adopted by EMA), MCDA (Multi-Criteria Decision Analysis — weighted scoring), FDA BR Framework (qualitative), UMBRA (Unified Methodologies for Benefit-Risk Assessment), IMI PROTECT BRA tools. Visual representations: BR value maps, effects tables, forest plots, net clinical benefit (NCB). PBRER (PSUR successor) includes integrated BR evaluation section. Lifecycle BR reassessment essential.

✔ Correct — C: BCPNN (Bandyopadhyay-Bate; WHO-UMC since 1998) = Bayesian Confidence Propagation Neural Network. Computes Information Component IC = log₂ [P(drug, event) / (P(drug) × P(event))]. Signal threshold: IC₀₂₅ > 0 (lower 95 % CI of IC above zero). Updates with new data (Bayesian prior + likelihood). Shrinkage toward null controls false positives with small cell counts. VigiMatch + VigiLyze apply to VigiBase. Complementary to PRR (frequentist). Modern machine-learning approaches (SIDER, OFFSIDES databases, graph-neural networks) emerging.

✔ Correct — A: PRR (Proportional Reporting Ratio, Evans 2001) = [a/(a+c)] / [b/(b+d)]; where 2×2 table: a = event reported with drug, b = same event with other drugs, c = other events with drug, d = other events with other drugs. MHRA UK threshold: PRR ≥ 2 + χ² ≥ 4 + n ≥ 3 → signal. ROR (Reporting Odds Ratio) = (a/c) / (b/d) = a×d / (b×c) — used by EudraVigilance. Both frequentist; Bayesian (BCPNN, GPS / MGPS) handles small counts better. Sensitivity: signal depends on notoriety + indication + confounding.

✔ Correct — A: PvPI launched 14 July 2010 by CDSCO + MoHFW. Initial coordinator AIIMS New Delhi (2010-11); transferred to Indian Pharmacopoeia Commission (IPC) Ghaziabad as National Coordination Centre (NCC-PvPI) since April 2011. Mission: safeguard patient safety through monitoring + analysis of ADRs of medicines used in India. Today 700+ ADR Monitoring Centres (AMCs) — medical colleges, hospitals, autonomous institutes. Earlier NPP (National Pharmacovigilance Programme 2004) preceded + discontinued; WHO PIDM membership since 1998.

✔ Correct — C: NCC-PvPI at Indian Pharmacopoeia Commission (IPC), Sector 23, Raj Nagar, Ghaziabad, UP — autonomous body under MoHFW. Functions: coordinate ADR data collection from 700+ AMCs; review, enter into VigiFlow; forward to WHO-UMC Uppsala VigiBase; signal detection; regulator recommendations (CDSCO); training (PV programs at TISS + other partners); publications (ADR Reporter quarterly newsletter); stakeholder engagement. Director IPC also heads NCC. Expert committees (Signal Review Panel, Safety Monitoring Board) advise CDSCO on label updates, restrictions, withdrawals.

✔ Correct — B: AMCs enter suspected ADR case data into VigiFlow (WHO-UMC web platform). NCC-PvPI reviews, codes in MedDRA, performs causality assessment + forwards to VigiBase. Additional routes: CDSCO paper form, ADR PvPI mobile app (patient / consumer reporting in English + Hindi; Android + iOS), toll-free helpline 1800-180-3024. PvPI also receives Medication Error reports via ME-PvPI form (separate from ADR). AMCs submit monthly reports; active periods during campaigns ("Safe Use Medicine Week"). NCC publishes monthly newsletter + quarterly "ADR Reporter".

✔ Correct — D: WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden since 1978; operated by Uppsala Monitoring Centre (UMC), an independent not-for-profit foundation. Hosts VigiBase, provides signal detection (VigiLyze, VigiMatch, VigiRank), develops WHO-DD (Drug Dictionary Enhanced), MedDRA interfaces, publishes Uppsala Reports, runs PV training courses worldwide. Partner in WHO PIDM. Board includes WHO + Swedish Medical Products Agency representation. UMC strategic partner to LMICs for PV capacity-building.

✔ Correct — A: VigiBase = WHO's global ICSR database, managed by WHO-UMC since 1968. Contains > 35 million ICSRs from 170+ countries (full PIDM members + associates). Grows by ~ 3 million/year. Uses WHO-DD Enhanced for drug coding + MedDRA for events. Free access for national PV centres via VigiLyze portal. Industry access via licensed partner. Signal detection tools: BCPNN (IC), VigiRank (weighted confidence), VigiMatch (duplicate detection). Data feeds signal detection, WHO publications + Global Individual Case Safety Reports Database.

✔ Correct — B: EudraVigilance (EV) = EMA's electronic system (since 2001, major upgrade 2017) for ICSR collection + signal detection in EU / EEA. Two modules: Post-Authorisation Module (EVPM), Clinical Trial Module (EVCTM). Receives SUSAR + ICSR from MAHs + national competent authorities (NCAs). Public access portal adrreports.eu. ROR for signal detection. Article 57 (Extended EudraVigilance Medicinal Product Dictionary — XEVMPD) requires MAH to submit medicinal product data. Linked to EU Risk Management Plan repository.

✔ Correct — C: FAERS (FDA Adverse Event Reporting System) = US FDA database of post-marketing ADR reports. Successor to AERS + earlier SRS. Sources: MedWatch 3500 (voluntary HCP / consumer), 3500A (mandatory manufacturer), IND AE reports. Public dashboard at fda.gov. Millions of reports since 1969. Used by FDA Sentinel + active signal detection (EBGM / EB05). VAERS = Vaccine Adverse Event Reporting System (CDC + FDA). MAUDE = Manufacturer + User Facility Device Experience (medical devices). FAERS data bias: media attention → reporting surge (notoriety effect).

✔ Correct — A: UK Yellow Card Scheme = MHRA (Medicines + Healthcare products Regulatory Agency) + Commission on Human Medicines post-thalidomide (1964, one of world's first spontaneous reporting schemes). Report routes: paper yellow card, website, Yellow Card app, 15-digit NHS ID linkage. Accepts reports from all HCPs + patients + public + MAH. Black triangle ▼ products: report all. Regular "Drug Safety Update" bulletin. Post-Brexit: MHRA independent but continues to exchange data with EMA. Complements the WHO ICSRs submitted to VigiBase.

✔ Correct — D: Professional societies: ISoP (International Society of Pharmacovigilance) — annual conference, journal Drug Safety, training + certifications; ISPE (International Society for Pharmacoepidemiology) — ICPE conference, Pharmacoepidemiology + Drug Safety journal; DIA (Drug Information Association) — global PV tracks at conferences; CIOMS — Council for International Organizations of Medical Sciences — issues white papers + working groups; IFPMA — International Federation of Pharmaceutical Manufacturers Associations. Journals: Drug Safety, Pharmacoepidemiology + Drug Safety, Expert Opinion on Drug Safety, WHO Uppsala Reports. India: SOPI (Society of Pharmacovigilance, India).

✔ Correct — B: Uppsala Reports = quarterly magazine from WHO Collaborating Centre for International Drug Monitoring (UMC) — free digital + print. Content: ADR signal reports, PV programmes in different countries, WHO-UMC news, guest commentaries, case highlights, training announcements. Complementary: WHO Drug Information (quarterly, Geneva). SIGNAL publication = weekly for VigiBase signal triage. India ADR Reporter (quarterly PvPI newsletter). Scientific journals: Drug Safety (ISoP), Pharmacoepidemiology + Drug Safety (ISPE), Expert Opinion on Drug Safety.

✔ Correct — C: India joined WHO Programme for International Drug Monitoring in 1998 as full member. Earlier initiatives: National Drug Monitoring Scheme 1986; AIIMS Delhi (1989) first regional centre; Mumbai + Chennai + Thiruvananthapuram added. NPP (National Pharmacovigilance Programme) 2004-2008 (WB-funded, discontinued). PvPI launched 2010 (post-NPP). IPC took NCC role 2011. India now among top contributors to VigiBase. PvPI celebrates 14 July as National Pharmacovigilance Day.

✔ Correct — A: National Pharmacovigilance Week observed annually in India 17-23 September; started 2016 to raise awareness of safe drug use + ADR reporting. Coincides with WHO Patient Safety Day (17 September since 2019). "Meri Pharmacovigilance Yatra" campaign. Also 14 July = PvPI Foundation Day (launch 2010). World Patient Safety Day theme: "Medication Without Harm". PvPI runs CME, workshops, poster competitions, media engagement, mobile app launches during this period. Related: World Health Day 7 April (WHO birthday); Human Rights Day 10 Dec.

✔ Correct — D: PvPI publishes Medicines Safety Newsletter + ADR Reporter (quarterly) with updates on regulatory actions, signal assessments, reporting statistics, awareness campaigns. Distributed to AMCs, regulators, healthcare professionals. Format: open-access PDF on IPC website. MHRA publishes "Drug Safety Update" monthly. WHO-UMC publishes Uppsala Reports. WHO Drug Information quarterly. FDA publishes Drug Safety Podcasts + Safety Communications. EMA publishes PRAC recommendations monthly.

✔ Correct — A: Clinical-trial PV: ICH E6 (Good Clinical Practice) + E2A (definitions + standards for expedited reporting). Sponsor duties: SUSAR 7-day fatal / LT, 15-day others, blinding preserved but unblinded when necessary, DSUR annual (E2F), Investigator Brochure Reference Safety Information (RSI), DMC / DSMB operations, IRB / IEC notification, coordinating investigators, Risk-Based Monitoring (RBM). India NDCT Rules 2019 require CDSCO + IEC notification within 14 days serious unexpected. Registry at CTRI (Clinical Trials Registry-India) + ClinicalTrials.gov. Post-trial access to study drug as part of ethical obligation.

✔ Correct — B: DSUR (Development Safety Update Report, ICH E2F 2010) = annual common format + content for clinical-trial safety reporting to regulators + IRBs / IECs. Analog to post-marketing PSUR / PBRER. Includes: worldwide cumulative patient exposure, summary of serious events, interim analyses, ongoing benefit-risk, significant regulatory actions. Replaces earlier IND Annual Reports (US) + Annual Safety Report (EU). Alongside DSUR, expedited SUSAR reporting continues (7 d / 15 d). First DSUR due 1 year after first authorisation in any country.

✔ Correct — C: EU GVP (Good Pharmacovigilance Practices) modules — EMA + European Commission published since 2012 under Regulation (EU) 1235/2010 + Directive 2010/84/EU. Sixteen modules (I-XVI) covering: PV systems + QMS, PV inspections, audits, PSMF, additional monitoring, management + reporting of ADRs, PSUR, signal management, additional risk-minimisation, periodic reports, interaction with public, PASS, product or population specific considerations (P.I vaccines, P.II biologicals, P.III pregnancy / lactation, etc.). Guide for MAH + regulators + HCPs. No direct US analog (FDA guidelines serve similar role).

✔ Correct — A: PRAC (Pharmacovigilance Risk Assessment Committee) = EMA scientific committee established 2012 under Reg 1235/2010. Responsible for assessing all aspects of pharmacovigilance risk management of human medicines. Members: 1 per EU member state + EEA + 6 independent experts + patient + HCP representatives. Monthly meetings. Outputs: PRAC recommendations → CHMP opinion → EC decision. Key activities: signal review, PSUR assessment, referrals (Article 31, 107i), RMP assessment, post-authorisation safety studies (PASS) protocols + results, safety communication.

✔ Correct — B: Modern PV scope: all medicinal products — chemical drugs, biologicals (recombinant proteins, mAbs, ATMPs gene / cell therapies), vaccines (via AEFI programme + VAERS US, Yellow Card UK), biosimilars, herbal / traditional medicines (including Ayurvedic — WHO herbal vigilance), blood + blood products (haemovigilance — France, UK + WHO Global Advisory Committee), medical devices (materiovigilance — MDR 2017 EU, MAUDE US, MDAMP India), cosmetics (cosmetovigilance), health food / supplements, radiopharmaceuticals. Each has specific reporting systems. India: AEFI programme under MoHFW, MvPI (Materiovigilance Programme of India, 2015).

✔ Correct — D: AEFI (Adverse Events Following Immunisation) = any untoward medical occurrence after immunisation, not necessarily causally related. India MoHFW AEFI programme under UIP (since 1988; revamped 2015). Classification (Brighton / WHO): vaccine-product related (pharmacological), vaccine-quality defect, immunisation error (cold-chain / technique), anxiety-related (vasovagal), coincidental. National AEFI Committee (CDSCO + MoHFW + ICMR + AIIMS + IPC + experts) reviews serious AEFIs. AEFI secretariat at Nirman Bhawan, Delhi. State + District AEFI committees. CIS (Causality Assessment Committee). Monitoring critical for public trust in vaccination.

✔ Correct — B: Materiovigilance Programme of India (MvPI) launched July 2015 by CDSCO + IPC Ghaziabad + NIB Noida — safety monitoring of medical devices in India. Now ~ 300+ Medical Device Adverse Event Monitoring Centres (MDMCs). Parallel to PvPI. Reports via Medical Device Adverse Event form (paper / online). Covers ~ 600 notified devices under Medical Devices Rules 2017. Similar programmes: HvPI (Haemovigilance, 2012; NIB Noida) for blood product safety; NPPCS (cosmetovigilance). Global analog: EU MDR 2017 (UDI + EUDAMED); FDA MAUDE.

✔ Correct — B: ICH E2C (R2) — Periodic Benefit Risk Evaluation Report (PBRER) replaced the traditional PSUR (Periodic Safety Update Report) in 2012. Shift from pure safety data to integrated benefit-risk assessment. Structure follows ICH E2C-R2 template with 20 sections (Executive Summary, worldwide MA status, actions taken for safety, changes to reference safety info, patient exposure, presentation of data, safety data findings, signal + risk evaluation, benefit evaluation, integrated benefit-risk analysis, conclusions). Frequency in EU: 6-monthly first 2 yr, annually next 2 yr, then 3-yearly; defined in EURD list (EU Reference Dates).

✔ Correct — C: Data Lock Point (DLP) = the cutoff date after which no new safety data are included in the PBRER / PSUR interval. All cases with receipt date ≤ DLP are included; later cases deferred to next report. EU EURD list harmonises DLP across MAHs for same active substance. Submission due 70 calendar days after DLP (interval ≤ 12 mo) or 90 days (> 12 mo). International Birth Date (IBD) = date of first MA anywhere globally — used as anchor for PBRER cycle.

✔ Correct — A: International Birth Date (IBD) = date of first marketing authorisation for a product anywhere in the world (by any regulatory authority). Anchors the PBRER reporting cycle so the same report can be used globally. MAH may request Harmonised Birth Date (HBD) if multiple products share substance. EURD list (EU) publishes harmonised DLPs + frequencies. IBD is per active substance, not formulation. Used to align reporting intervals internationally.

✔ Correct — D: EU GVP Module VII default frequency for new products: 6-monthly for first 2 yr, annually next 2 yr, then 3-yearly. Exact DLP + frequency defined in EURD (EU Reference Dates) list published by EMA (updated monthly). Exceptions: new active substance, reference PBRERs, additional monitoring (black triangle ▼), or regulator-directed increase after safety signal. Generic / well-established products may be PBRER-exempt unless specifically required.

✔ Correct — B: Risk Management Plan (RMP) — mandatory document in EU (GVP Module V) submitted with every new MA (since 2005, updated 2012). Core parts: (I) product overview, (II) safety specification (important identified risks + important potential risks + missing information), (III) PV plan (routine + additional studies = PASS), (IV) plans for post-authorisation efficacy studies (PAES), (V) risk-minimisation measures (routine = SmPC + PIL; additional = DHPC + educational materials + controlled distribution + pregnancy-prevention programme + patient alert card), (VI) summary. Updated throughout lifecycle. US analog: REMS. India NDCT 2019 requires RMP for new drugs.

✔ Correct — C: RMP Part II Safety Specification = (i) important identified risks — ADRs with sufficient evidence of association; (ii) important potential risks — preliminary evidence but unconfirmed; (iii) missing information — gaps in knowledge (e.g. use in pregnancy, paediatrics, hepatic / renal impairment, long-term use, elderly, drug interactions). Drives the PV plan (Part III) with routine and additional activities (PASS, registries). Structure per GVP Module V format.

✔ Correct — A: REMS = Risk Evaluation and Mitigation Strategy — FDA risk-management framework mandated under the FDA Amendments Act (FDAAA 2007). Three possible components: (i) Medication Guide / Patient Package Insert; (ii) Communication Plan (Dear HCP letter, professional society outreach); (iii) ETASU — Elements to Assure Safe Use (prescriber certification, pharmacy certification, patient enrolment, REMS registry, restricted distribution, lab monitoring). Examples: isotretinoin iPLEDGE, clozapine REMS, thalidomide / lenalidomide REMS, mifepristone REMS, TIRF-REMS (fentanyl rapid-onset). All REMS have REMS Assessment reports (at 18 mo, 3 yr, 7 yr).

✔ Correct — B: ETASU = Elements to Assure Safe Use. Restrictive REMS component for products with serious safety concerns. Measures: prescriber training + certification, pharmacy enrolment, patient enrolment in registry, documentation of safe-use conditions (negative pregnancy test, informed consent), restricted distribution network, lab monitoring prior to dispensing, periodic safety checks. Example: iPLEDGE (isotretinoin) requires monthly pregnancy test + 2 forms of contraception + patient counselling. Clozapine REMS requires ANC monitoring. Thalidomide / lenalidomide REMPATE programmes.

✔ Correct — D: DHPC (Direct / Dear Healthcare Professional Communication, also called Dear Doctor Letter) — urgent safety communication from MAH to prescribers + pharmacists when a significant new safety issue is identified (contraindication, new warning, restriction, withdrawal, counterfeit alert). EU GVP Module XV governs DHPC — requires EMA / NCA approval before dissemination, standardised structure (background, summary of new information, recommendations for prescriber + patient, further actions, contact + reporting details). US: Dear Health Care Provider Letter. India CDSCO / PvPI issues Drug Safety Alerts. Sent via fax, post, email, professional societies, regulator website.

✔ Correct — A: Inverted black triangle (▼) — EU symbol since 2013 (EU Regulation 1235/2010, GVP Module X) marking medicines under Additional Monitoring. Printed on SmPC + Package Leaflet with statement: "This medicinal product is subject to additional monitoring." Criteria: new active substance authorised after 1 Jan 2011, biologicals, conditional / exceptional authorisation, obligation to conduct PASS, request for additional monitoring. Encourages HCP + patient reporting. Stays for at least 5 yr. EMA maintains a public list. UK MHRA uses same symbol.

✔ Correct — B: PASS = Post-Authorisation Safety Study — conducted after MA to identify, characterise, or quantify a safety hazard; confirm safety profile; or measure effectiveness of risk-minimisation measures. Two types: (i) imposed PASS (regulator requires, legal obligation); (ii) voluntary PASS (MAH-initiated). Designs: cohort, case-control, cross-sectional, drug-utilisation, registries, active surveillance. Protocols submitted to PRAC before initiation. Results reported in PBRER + separate study report. ENCePP — European Network of Centres for Pharmacoepidemiology and Pharmacovigilance — provides ENCePP code of conduct, EU PAS Register (> 3800 registered PASS).

✔ Correct — C: ENCePP = European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (launched 2007, coordinated by EMA). Network of > 200 research + PV centres across Europe. Key deliverables: ENCePP Code of Conduct (methodological + transparency standards for PASS); EU PAS Register (publicly searchable database of PASS protocols + results); ENCePP Guide on Methodological Standards; Checklist for Study Protocols. Promotes high-quality non-interventional studies, data transparency, and reproducible methodology in PV.

✔ Correct — A: PSMF (PV System Master File, GVP Module II) — detailed description of the MAH's pharmacovigilance system. Mandatory in EU since 2012 (replaced DDPS). Owned + maintained by MAH at the location where main PV activities (or QPPV) are performed. Content: QPPV details + deputy, PV organisational structure, sources of safety data, IT systems (Oracle Argus, ArisGlobal LSMV, Veeva Vault), written procedures (SOPs), PV system performance (KPIs), QMS, record management. Available to regulators on request (within 7 days in EU). Summary included in e-application form; index submitted to EMA.

✔ Correct — D: QPPV (GVP Module I) — legally mandated individual responsible for the PV system of a MAH in EU; must reside + be operational in EU/EEA; single point of contact 24 / 7 for regulators; oversees PV system performance; has authority over PSMF, signal detection, ICSRs, PBRER, RMP. Qualifications: appropriate medical / life-sciences + PV experience (typically physician or pharmacist, but not legally restricted). Deputy QPPV recommended. Contact details submitted to EMA. Regulators may impose fines / MA suspension for QPPV-related non-compliance.

✔ Correct — C: Routine risk-minimisation = SmPC (Summary of Product Characteristics — for prescribers) + PIL / Package Leaflet (for patients) + labelling + legal status (Rx vs OTC) + pack-size limits. This is the default + default-sufficient layer. Additional risk-minimisation (when routine insufficient): Dear HCP Communication (DHPC), educational materials (prescriber + patient guides), patient alert card, controlled access programme, pregnancy-prevention programme (iPLEDGE analog), restricted distribution, prescriber certification. Effectiveness measured via PASS / questionnaires to prescribers / drug-utilisation studies.

✔ Correct — B: PV inspections (GVP Module III) — conducted by regulators (EMA, NCAs, MHRA, FDA) to verify MAH compliance with PV legal obligations. Assess PSMF, QPPV, QMS, SOPs, ICSR intake + processing, signal detection, PBRER / RMP compliance, training records, IT validation, outsourcing oversight, CAPA. Two types: routine (risk-based cyclic) or for-cause (triggered by signals, complaints, changes). Findings classified Critical / Major / Minor — Critical may trigger MA suspension / fines. Outcomes escalated to PRAC + CHMP. ICH E2E outlines PV inspections internationally.

✔ Correct — A: CIOMS VI (Council for International Organizations of Medical Sciences, Working Group VI, 2005) — "Management of Safety Information from Clinical Trials" — global harmonised recommendations for trial safety monitoring, IB safety update, DSMB governance, DSUR, reference safety information (RSI), SUSAR reporting 7 / 15 d. Other key CIOMS reports: CIOMS I (international reporting of ADR, yellow form), CIOMS II (PSUR framework → evolved into ICH E2C), CIOMS III (core data sheet → CCSI / CCDS), CIOMS V (practical aspects), CIOMS VII (DSUR), CIOMS VIII (signal detection), CIOMS X (evidence synthesis), CIOMS IX (risk minimisation measurement).

✔ Correct — D: PRAC — Pharmacovigilance Risk Assessment Committee — established July 2012 by EU PV legislation (Directive 2010/84/EU + Regulation 1235/2010); part of EMA. Responsible for all aspects of risk management of human medicines: detecting + assessing + understanding + communicating risks; RMP review; PASS protocol assessment; PSUSA (PSUR single assessment); signal evaluation; urgent safety procedures; inspection reports; Additional Monitoring list; referrals. Meets monthly, publishes recommendations that feed into CHMP (centrally authorised products) or CMDh (nationally authorised). 36 members — 1 per MS + 6 experts + 1 HCP + 1 patient rep + 1 Commission.

✔ Correct — B: Benefit-risk assessment = structured evaluation of all favourable (efficacy + patient-reported outcomes + public-health impact) vs unfavourable (ADR frequency + severity + reversibility + missing information) effects of a medicine in its approved indication, population, + conditions of use. Performed at MA (initial B-R), PSUR / PBRER (periodic re-assessment), signal evaluation, + regulatory referrals. Structured frameworks: EMA Effects Table, FDA B-R Framework (2013), PrOACT-URL (UoL), BRAT (Benefit-Risk Action Team), MCDA (multi-criteria decision analysis). Visual tools: value tree, effects table, forest plot, CHMP assessment report.

✔ Correct — C: WHO defines PV as "the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problems" — with the ultimate goal of protecting public health by promoting the safe and effective use of medicines. Achieved through ADR surveillance, signal detection, benefit-risk evaluation, risk minimisation, communication with HCPs + patients, and regulatory action. Supports rational pharmacotherapy, reduces preventable morbidity / mortality, and informs evidence-based prescribing throughout a medicine's lifecycle.