Pharmacovigilance · Myth Meets Molecules

1

Key Definitions

Core PV Terminology ▾

Term	Definition
Adverse Drug Reaction (ADR)	A response to a medicine which is noxious and unintended, occurring at doses normally used for prophylaxis, diagnosis or therapy. (WHO, 1972)
Adverse Event (AE)	Any untoward medical occurrence in a patient administered a pharmaceutical product — does not necessarily have a causal relationship with the treatment.
Side Effect	Any unintended effect occurring at therapeutic doses; related to the pharmacological properties of the drug.
Toxic Effect	Harmful effect from a dose higher than normally used.
SAE (Serious AE)	Results in: death · life-threatening · inpatient hospitalisation · persistent disability · congenital anomaly · medically significant event.
SUSAR	Suspected Unexpected Serious Adverse Reaction — a SAR not consistent with the Reference Safety Information.
Signal (WHO)	Reported information on a possible causal relationship between an AE and a drug, previously unknown or incompletely documented. Typically requires ≥ 3 case reports as a minimum threshold.
Pharmacovigilance (WHO)	The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problem.
Dechallenge	Withdrawal of the suspected drug — positive dechallenge = reaction improves/resolves after stopping.
Rechallenge	Re-administration of the suspected drug — positive rechallenge = reaction reappears. (Often ethically restricted)
ICSR	Individual Case Safety Report — the standard unit of ADR reporting in global databases.
DHPC	Direct Healthcare Professional Communication — urgent safety message sent directly to prescribers.

2

ADR Classification

Rawlins-Thompson Classification (A–F) ▾

Type	Name	Description & Key Example	Features
A	Augmented	Dose-dependent, predictable from pharmacology, common, low mortality. Example: Hypoglycaemia with insulin	Dose-↑ = risk-↑
B	Bizarre	Dose-independent, unpredictable, uncommon, high mortality. Example: Anaphylaxis with penicillin	Idiosyncratic; immune
C	Chronic	Related to cumulative dose / long-term use. Example: HPA suppression with steroids; Amiodarone pulmonary fibrosis	Cumulative-dose dependent
D	Delayed	Occurs after a delay; often dose-related. Example: Carcinogenesis with cyclophosphamide; thalidomide teratogenesis	Lag period after exposure
E	End-of-use	Occurs on withdrawal. Example: Opioid withdrawal syndrome; benzodiazepine withdrawal	Stops on reinstatement
F	Failure	Unexpected failure of therapy; often dose-related; caused by drug interactions. Example: OCP failure with rifampicin	Interaction-mediated

DoTS Classification (Dose · Time · Susceptibility) ▾

DoTS classifies ADRs along three independent axes:

Axis	Categories
Dose-relatedness	Toxic (supratherapeutic dose) · Collateral (occurs at therapeutic dose — expected pharmacology) · Hypersusceptibility (subtherapeutic dose, due to patient susceptibility)
Time-course	Time-independent (can occur any time) · First-dose · Intermediate (during early course) · Late/Delayed · Withdrawal · Long-term
Susceptibility	Age · Sex · Genetic polymorphisms · Co-morbidities · Drug interactions

Example (DoTS): Thalidomide phocomelia — Dose: Hypersusceptibility (foetus at therapeutic dose) · Time: Intermediate (first trimester) · Susceptibility: Foetal developmental stage

3

Causality Assessment Scales

WHO-UMC Causality Assessment Scale ▾

The most widely used causality tool in routine pharmacovigilance — used in VigiBase, PVPI. Scale: Certain → Probable → Possible → Unlikely → Conditional → Unassessable.

Category	Full Criteria	Key Point
CERTAIN	Plausible time sequence · Dechallenge positive · Rechallenge positive · Alternative cause excluded · Pharmacologically plausible	All 5 criteria met. Rechallenge positive is key — but NOT mandatory alone for 'Certain'.
PROBABLE / LIKELY	Reasonable time sequence · Dechallenge positive · Unlikely attributed to disease/other drugs · Rechallenge NOT required	No rechallenge needed; dechallenge positive is sufficient.
POSSIBLE	Reasonable time sequence · Could be explained by disease/other drugs · Dechallenge absent or unclear	Alternative cause cannot be excluded.
UNLIKELY	Time sequence improbable · Better explained by disease or other drugs	Causality considered remote.
CONDITIONAL / UNCLASSIFIED	Event not yet assessable; more data needed or data under examination	Data awaited — a relationship is not impossible.
UNASSESSABLE / UNCLASSIFIABLE	Insufficient or contradictory data; cannot be evaluated	Data quality prevents assessment even if more data arrives.

Mnemonic — WHO-UMC order

C-P-P-U-C-U → Certain · Probable · Possible · Unlikely · Conditional · Unassessable

★ PVPI (India) uses WHO-UMC as the primary causality tool.
★ WHO-UMC / Naranjo agreement is weak (Kappa = 0.463 — they often disagree).

Modified Karch-Lasagna (Schumacher) Scale ▾

Category	Definition
Definite	Reasonable temporal sequence · Recognised phenomenon · Dechallenge positive · Confirmed by rechallenge
Probable	Reasonable temporal sequence · Recognised phenomenon · Dechallenge positive · Rechallenge not done
Possible	Reasonable temporal sequence · May have been produced by patient condition or other drugs
Conditional	Temporal sequence reasonable · Not characteristic · Dechallenge equivocal · Explanation possible
Doubtful	Temporal relationship improbable · Other explanations more likely

4

Naranjo Algorithm (ADR Probability Scale)

10-Question Scoring Table ▾

Published by Naranjo et al. (1981). Score range: −4 to +13.

Question	Yes	No	Key Point / Trick
1. Previous conclusive reports on this reaction?	+1	0	Known documented ADR
2. AE appeared after the suspected drug?	+2	−1	Temporal link — highest positive weight; 'No' gives NEGATIVE score
3. AE improved when drug stopped or specific antidote given?	+1	0	Positive dechallenge
4. AE reappeared when drug was re-administered?	+2	−1	Rechallenge positive — strongest finding; ethically restricted
5. Are there alternative causes that could fully explain the reaction?	−1	+2	'No alternative cause' = +2 — key discriminating question
6. AE reappeared when a placebo was given?	−1	+1	Only question where 'No' → positive score (+1)
7. Drug detected in blood/fluids in toxic concentrations?	+1	0	Objective laboratory evidence
8. AE more severe when dose ↑ or less severe when dose ↓?	+1	0	Dose-response relationship
9. Similar reaction to same or similar drug before?	+1	0	Prior hypersensitivity or ADR history
10. AE confirmed by objective evidence?	+1	0	Lab result, biopsy, imaging, ECG, etc.

Total Score	ADR Probability
≥ 9	DEFINITE ADR
5 – 8	PROBABLE ADR
1 – 4	POSSIBLE ADR
≤ 0	DOUBTFUL ADR

High-yield tricks:
• Q2 & Q4 carry the highest individual weight (+2 each).
• Q6 is the only question where answering "No" gives a positive score (+1).
• Q5 "No alternative cause" = +2 — most discriminating for causality.
• Max = +13 · Min = −4

5

Hartwig & Siegel Severity Assessment Scale

7-Level Classification (Hartwig & Siegel, 1992) ▾

Level	Category	Full Criterion
1	MILD	ADR occurs but does NOT require any change in treatment with the suspected drug.
2	MILD	Drug withheld / discontinued / changed · No antidote required · No hospitalisation · No prolonged stay.
3	MODERATE	As Level 2 AND: (a) antidote/specific treatment needed; OR (b) hospitalisation required; OR (c) stay prolonged ≥ 1 day.
4	MODERATE	As Level 3 AND: clinically significant condition needing intensive management; OR permanent harm/disability; OR prolonged hospitalisation.
5	SEVERE	Requires intensive medical care (e.g., ICU) · Patient condition LIFE-THREATENING due to ADR.
6	SEVERE	ADR indirectly / contributorily caused the patient's death (contributing factor, not sole cause).
7	SEVERE	ADR is the PRIMARY, DIRECT cause of the patient's death.

Mnemonic — Severity levels

1–2 MILD | 3–4 MODERATE | 5–6–7 SEVERE

★ Level 3 = needs hospitalisation. Level 4 = needs ICU / intensive treatment OR permanent harm.
★ Level 6 = contributed to death. Level 7 = direct cause of death. (Key distinction!)

6

Schumock-Thornton Preventability Scale

Preventability Criteria (Schumock & Thornton, 1992) ▾

Assesses preventability — not causality or severity. Apply after confirming the ADR.

DEFINITELY PREVENTABLE — Answer YES to ≥ 1 of these 7 questions

Q1. Documented history of allergy or previous ADR to the same drug in patient's notes.
Q2. Drug prescribed was inappropriate / not indicated for patient's clinical condition.
Q3. Dose, route, or frequency inappropriate for age, weight, or disease state.
Q4. Required TDM or necessary laboratory monitoring was NOT performed.
Q5. Serum drug level documented as toxic prior to the ADR occurring.
Q6. Known drug-drug, drug-disease, or drug-food interaction present — drug still prescribed.
Q7. Patient non-compliant with the prescribed drug regimen.

PROBABLY PREVENTABLE — Answer YES to ≥ 1 (does NOT meet Definitely Preventable)

Q1. TDM required but levels not measured or abnormal level not acted upon.
Q2. Drug dose NOT adjusted for documented renal or hepatic impairment.
Q3. Less well-established drug interaction contributed to ADR.
Q4. Safer or more appropriate drug alternative was available for the indication.

NOT PREVENTABLE — None of the above criteria apply

Q1. Appropriate drug, correct dose/route/frequency, proper monitoring, compliant patient — ADR still occurred.
Q2. Inherently unpredictable (Type B / idiosyncratic) reaction — unavoidable with current medical knowledge.

Key rule: "TDM not performed" = Definitely Preventable (Q4). This is a common exam trap.

7

PVPI, Databases & Signal Detection

Pharmacovigilance Programme of India (PVPI) ▾

Parameter	Details
Established	2010 (initially 2004 as a pilot)
Nodal Agency (NCC)	Indian Pharmacopoeia Commission (IPC), Ghaziabad
Regulatory Authority	Central Drugs Standard Control Organisation (CDSCO), New Delhi
Structure	IME (Institutional Monitoring Centre) → AMC (Area Monitoring Centre) → NCC (IPC)
Reporting portal	VigiFlow (National ADR Monitoring System)
ADR reporting form	Yellow / Suspected ADR Reporting Form (now online via VigiFlow)
Who can report?	Healthcare professionals, patients, and caregivers — voluntary reporting
WHO PIDM membership	India joined WHO Programme for International Drug Monitoring in 1998
Causality tool used	WHO-UMC scale (primary)

Global PV Databases ▾

VigiBase

WHO Global ICSR database. Maintained by Uppsala Monitoring Centre (UMC), Uppsala, Sweden.

VigiFlow

WHO web-based ICSR reporting tool used by national centres including PVPI.

VigiAccess

Public access to WHO global ADR data — open to patients and prescribers.

FAERS (USA)

FDA Adverse Event Reporting System. Renamed from AERS in 2012. Uses MGPS/EBGM method.

EudraVigilance

EMA's pharmacovigilance database — Europe. Uses ROR for signal detection.

Yellow Card (UK)

MHRA spontaneous ADR reporting system, United Kingdom.

MedWatch (USA)

FDA safety information and ADR reporting portal.

Signal Detection Methods ▾

Method	Used By	How it works / Threshold
PRR (Proportional Reporting Ratio)	EMA, MHRA	Compares proportion of a specific ADR for a drug vs all drugs. Signal if PRR ≥ 2 with lower bound 95% CI > 1. Frequentist.
ROR (Reporting Odds Ratio)	EMA / EudraVigilance	Odds of reporting a specific ADR with a drug vs all other ADRs. Frequentist method.
BCPNN (Bayesian Confidence Propagation Neural Network)	WHO / VigiBase (UMC)	Generates Information Component (IC). Signal if IC025 > 0.
MGPS (Multi-item Gamma Poisson Shrinker)	FDA / FAERS	Generates EBGM score. Signal if EBGM05 ≥ 2.

Signal ≠ Causality. Disproportionality signals indicate association. Further causality assessment follows: Signal Validation → Strengthening → Risk Assessment → Regulatory Action (DHPC / label update / REMS / withdrawal).

8

Pharmacogenomics & Regulatory Timelines

HLA & Enzyme Variants — High-Yield ADR Associations ▾

Gene / Variant	Drug	ADR	Notes
HLA-B*57:01	Abacavir	Hypersensitivity reaction (AHR)	~8% of Caucasians. Mandatory pre-screening. REMS required. Rechallenge CONTRAINDICATED — potentially fatal.
HLA-B*15:02	Carbamazepine	Stevens-Johnson Syndrome (SJS)	Common in South/Southeast Asian populations (South Indian Tamils). Mandatory screening in Taiwan/Thailand.
HLA-B*58:01	Allopurinol	SJS / TEN	Southeast Asian patients. Mandatory screening in some Asian countries.
G6PD deficiency	Primaquine, Dapsone, Nitrofurantoin	Haemolytic anaemia	X-linked; screen before antimalarials in endemic regions.
CYP2D6 poor metaboliser	Codeine / Tramadol	Morphine toxicity (opioid overdose)	Poor metaboliser = no conversion to active morphine → accumulation if prodrug bypassed; Ultra-rapid = excess morphine.
CYP2C19 poor metaboliser	Clopidogrel	Reduced antiplatelet effect → thrombosis	Clopidogrel is a prodrug requiring CYP2C19 activation. Poor metaboliser = increased thrombotic risk.
TPMT deficiency	Azathioprine / 6-MP	Severe myelosuppression	TPMT deficient patients accumulate 6-TGN → bone marrow toxicity. Screen before starting.
UGT1A1*28	Irinotecan	Severe diarrhoea, neutropaenia	Reduced glucuronidation of active metabolite SN-38 → toxicity.

Clinical Development Phases & Regulatory Reporting Timelines ▾

Phase	Population	Key Features
Preclinical	Animals	Toxicity, PK/PD, pharmacodynamics — no human exposure
Phase 0	~10 healthy volunteers	Microdosing (<1/100 of therapeutic dose) · No therapeutic intent · Exploratory
Phase I	20–80 healthy volunteers	Safety, dosing, PK/PD · First-in-human · Dose escalation
Phase II	100–300 patients	Efficacy, side effects, dose-range finding
Phase III	1000–3000+ patients	Randomised controlled trials · Pivotal for approval
Phase IV	General population	Post-marketing surveillance · Real-world ADR monitoring · PSUR

Report Type	Timeframe
Fatal / life-threatening SUSAR (clinical trial)	7 calendar days (expedited)
Other serious unexpected SARs (clinical trial)	15 calendar days (expedited)
PSUR submission frequency	Every 6 months (first 2 years) → annually (next 3 years) → as per licensing authority
IND Safety Report — unexpected serious ADR (USA)	15 calendar days
NDA/BLA post-marketing — serious unexpected ADR (USA)	15-day alert report

9

Case Scenarios & MCQ Bank

Case 01

ACE Inhibitor Cough — Enalapril

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A 45-year-old male hypertensive patient was started on Enalapril 5 mg OD. Three weeks later he developed a dry, persistent, non-productive cough. The drug was stopped; the cough resolved completely within 2 weeks. A year earlier, the same patient had developed a similar cough when prescribed Lisinopril, which also resolved on stopping.

Apply the Naranjo Algorithm — calculate the score

Q1 (previous reports): +1 (ACE inhibitor cough is well-documented)
Q2 (AE after drug): +2
Q3 (improved on dechallenge): +1
Q4 (rechallenge positive): +2 — prior Lisinopril exposure counts as positive rechallenge with a similar drug
Q5 (no alternative cause): +2 (cough resolved with drug switch, not disease treatment)
Q9 (similar prior reaction): +1 (Lisinopril history)

Total = 9 → DEFINITE ADR

WHO-UMC Causality Classification

CERTAIN — Plausible time sequence ✓ · Dechallenge positive ✓ · Rechallenge positive (Lisinopril history) ✓ · Alternative cause excluded ✓ · Pharmacologically plausible (bradykinin accumulation) ✓

Hartwig Severity

Level 2 — MILD (requires drug withdrawal but no hospitalisation, no antidote needed)

Pharmacological mechanism

ACE inhibitors block bradykinin degradation → bradykinin accumulates in airways → stimulates bronchial C-fibres → dry cough. ARBs (Losartan) do NOT cause cough — they do not affect bradykinin metabolism.

Case 02

Carbamazepine-induced SJS/TEN — HLA-B*15:02

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A 28-year-old South Indian Tamil woman developed fever, widespread skin blistering involving >30% BSA, and mucous membrane involvement on Day 14 of starting Carbamazepine for trigeminal neuralgia. She required 3 weeks of ICU care and was discharged with residual ocular scarring.

ADR diagnosis and relevant genetic test

Stevens-Johnson Syndrome / TEN overlap (SJS/TEN).
Test: HLA-B*15:02 — strongly associated with carbamazepine-induced SJS/TEN in South/Southeast Asian populations. Common in South Indian Tamils.

Hartwig Severity

Level 6 — SEVERE (contributed to permanent harm — ocular scarring — AND required ICU / intensive medical care; condition was life-threatening). Note: Level 7 would apply if death occurred.

WHO-UMC Causality

PROBABLE/LIKELY — plausible time sequence (Day 14), dechallenge positive, consistent with known drug reaction. Rechallenge NOT done (would be unethical and potentially fatal).

SCORTEN score

SCORTEN (SCORe of Toxic Epidermal Necrolysis) predicts TEN mortality. Parameters: age >40 · malignancy · HR >120 · initial BSA detachment >10% · serum urea >10 mM · serum glucose >14 mM · bicarbonate <20 mM. Score ≥ 5 → mortality >90%.

Case 03

Metformin-associated Lactic Acidosis (MALA)

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A 60-year-old diabetic man on Metformin 1g BD received IV contrast for a CT scan. He was NOT advised to stop Metformin beforehand. 48 hours post-procedure: nausea, vomiting, abdominal pain, confusion. ABG: pH 7.18 · Lactate 8 mmol/L · Anion gap 24 mEq/L.

ADR identification and Rawlins-Thompson classification

Metformin-associated lactic acidosis (MALA). Type C (Chronic/dose-related) — risk accumulates with impaired renal elimination; IV contrast causes transient AKI, reducing Metformin clearance → lactic acid accumulation.

Prevention

Metformin should be STOPPED 48 hours BEFORE IV contrast and restarted only after renal function is confirmed normal (≥ 48 hours post-procedure). As per ESUR and ACR guidelines.

Hartwig Severity

Level 5 — SEVERE (life-threatening; required intensive medical management).

Naranjo Score

Score ≈ 7–8 (Probable ADR): Q1 +1 (known reaction) · Q2 +2 · Q3 +1 (improved with withdrawal/treatment) · Q5 +2 (no other cause) · Q10 +1 (ABG/lactate confirms diagnosis).

Case 04

Signal Detection — Anti-epileptic & Aplastic Anaemia

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A pharmacovigilance review detects a signal in VigiBase showing a disproportionate association between a new anti-epileptic drug and aplastic anaemia. PRR = 6.4 (95% CI: 3.1–13.2) · IC025 = 2.1.

WHO definition of a 'signal'

Reported information on a possible causal relationship between an AE and a drug, previously unknown or incompletely documented. Typically requires ≥ 3 case reports as a minimum threshold.

Interpret PRR = 6.4 and IC025 = 2.1

PRR 6.4 (CI lower bound 3.1 > 1) → Positive signal — the drug is 6.4× more likely associated with aplastic anaemia than other drugs. IC025 = 2.1 > 0 → Positive BCPNN signal (WHO VigiBase threshold met). Both methods confirm disproportionate reporting.

Post-signal actions

Signal Validation → Signal Strengthening (causality assessment, biological plausibility) → Risk Assessment → Regulatory Action: DHPC · label update · REMS · or market withdrawal.

Case 05

Abacavir Hypersensitivity — HLA-B*57:01

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A 35-year-old HIV-positive patient on Abacavir-containing ART for 6 weeks presents with fever, rash, myalgia, nausea, and respiratory symptoms. All symptoms resolved within 72 hours of stopping Abacavir.

Key genetic marker — was pre-treatment testing done?

HLA-B*57:01 present in ~8% of Caucasians. Current WHO/BHIVA guidelines mandate HLA-B*57:01 screening before starting Abacavir. If positive → Abacavir is CONTRAINDICATED.

Can we rechallenge with Abacavir?

ABSOLUTELY NOT. Rechallenge after confirmed AHR is contraindicated and potentially fatal — can cause hypotension, bronchospasm, and death within hours. This is a REMS (Risk Evaluation and Mitigation Strategy) requirement for Abacavir.

WHO-UMC Causality

CERTAIN — Consistent time sequence · Dechallenge positive (resolved in 72 hours) · Pharmacologically plausible · No alternative explanation.

Hartwig Severity

Level 3 — MODERATE (required hospitalisation for assessment and monitoring, though resolved completely).

MCQ Bank — 10 Practice Questions ▾

Q1. A patient on Isoniazid develops peripheral neuropathy after 3 months. Which mechanism is responsible?

A) Direct neurotoxicity of INH

B) Competitive inhibition of pyridoxal phosphate (Vitamin B6) ✓

C) INH-induced SLE

D) Reactive oxygen species generation

INH is structurally similar to pyridoxine — it inhibits pyridoxal phosphate, essential for peripheral nerve function. This is a Type A (dose-related, predictable) ADR. Prophylactic Vitamin B6 is given to high-risk patients.

Q2. In the Naranjo algorithm, which question, if answered 'No', gives a POSITIVE score?

A) Q1: Previous conclusive reports

B) Q5: Alternative causes present

C) Q6: Did the reaction reappear when placebo given ✓

D) Q9: Similar prior reaction

Q6: If placebo did NOT cause the reaction (No = +1), this strengthens the case for the drug. This is the only Naranjo question where 'No' gives a positive score.

Q3. Which Hartwig severity level describes an ADR requiring ICU admission but patient ultimately recovers with no permanent harm?

A) Level 3

B) Level 4

C) Level 5 ✓

D) Level 6

Level 5 = SEVERE: life-threatening ADR requiring intensive care. Level 4 = MODERATE (clinically significant/ICU but not life-threatening). Level 6 = contributed to death. No death → not Level 6 or 7.

Q4. India's National Co-ordination Centre for Pharmacovigilance is located at:

A) CDSCO, New Delhi

B) IPC, Ghaziabad ✓

C) AIIMS, New Delhi

D) ICMR, New Delhi

Indian Pharmacopoeia Commission (IPC), Ghaziabad = National Co-ordination Centre (NCC) for PVPI. CDSCO = regulatory authority only.

Q5. Long-term amiodarone causing thyroid dysfunction and pulmonary fibrosis is best classified as:

A) Type A

B) Type B

C) Type C ✓

D) Type D

Type C (Chronic) — related to cumulative dose and long-term use. Amiodarone toxicities depend on total cumulative dose and duration of therapy.

Q6. Which statistical method does the Uppsala Monitoring Centre use for signal detection in VigiBase?

A) Proportional Reporting Ratio (PRR)

B) Reporting Odds Ratio (ROR)

C) Bayesian Confidence Propagation Neural Network (BCPNN) ✓

D) Multi-item Gamma Poisson Shrinker (MGPS)

UMC/WHO uses BCPNN → IC. Signal when IC025 > 0. MGPS (EBGM) = FDA/FAERS. PRR/ROR = EMA/MHRA (frequentist).

Q7. Congenital limb defects when mother takes drug in first trimester (thalidomide). DoTS classification?

A) Dose-related, Time-independent

B) Hypersusceptibility (foetal age), Time-dependent (intermediate) ✓

C) Collateral, Time-independent

D) Non-dose-related, time-independent

Dose: Hypersusceptibility (therapeutic dose in susceptible foetus during organogenesis). Time: Time-dependent — specifically first trimester. Susceptibility: foetal developmental stage.

Q8. WHO-UMC 'CONDITIONAL/UNCLASSIFIED' means:

A) Causality is definite but assessment is incomplete

B) Insufficient or contradictory data — cannot be evaluated

C) Event could be due to drug or disease

D) More data needed but a relationship is not impossible ✓

Conditional/Unclassified = event not assessable; data awaited or under examination — a relationship is NOT impossible. Contrast with Unassessable = data insufficient/contradictory — cannot be evaluated even with more data.

Q9. HLA-B*57:01 screening before starting Abacavir is mandatory because:

A) It predicts virological response

B) It predicts drug resistance mutations

C) It identifies patients at risk of life-threatening hypersensitivity ✓

D) It determines optimal dosing schedule

HLA-B*57:01 presence confers ~55% risk of AHR (vs <1% in negative patients). Reaction can be fatal on rechallenge. Mandatory screening mandated by FDA, EMA, WHO. Contraindicated if positive.

Q10. PRR = 8.5 (95% CI lower bound 4.2). What does this indicate?

A) Negative signal — no association

B) Positive disproportionality signal ✓

C) Causality is proven

D) The drug is the definite cause

PRR ≥ 2 with lower bound of 95% CI > 1 = positive signal. PRR 8.5 (lower bound 4.2, well above 1) = strong disproportionate reporting. IMPORTANT: signals indicate association, NOT proven causation.

10

Rapid-Fire Q&A & High-Yield Facts

50-Question Rapid-Fire Bank ▾

01 Maximum possible Naranjo score?

13

02 Minimum possible Naranjo score?

−4

03 Naranjo Definite ADR requires score of?

≥ 9

04 Naranjo Probable ADR range?

5–8

05 Naranjo Possible ADR range?

1–4

06 Naranjo Doubtful ADR range?

≤ 0

07 WHO-UMC category requiring rechallenge positivity?

Certain (as one criterion — not mandatory alone)

08 WHO-UMC when data is insufficient/contradictory?

Unassessable / Unclassifiable

09 Hartwig Level 7 means?

ADR is the direct (primary) cause of death

10 Hartwig Level 6 means?

ADR contributed to death (not sole cause)

11 Hartwig Levels 1–2 = ? severity

Mild

12 Hartwig Levels 3–4 = ? severity

Moderate

13 Hartwig Levels 5–7 = ? severity

Severe

14 PVPI nodal centre in India?

IPC, Ghaziabad

15 Global WHO ADR database?

VigiBase

16 WHO-UMC Uppsala Monitoring Centre is in?

Uppsala, Sweden

17 India joined WHO PIDM in which year?

1998

18 PVPI established in which year?

2010

19 ACE inhibitor cough mechanism?

Bradykinin accumulation

20 HLA type for Abacavir hypersensitivity?

HLA-B*57:01

21 HLA type for Carbamazepine SJS in Asians?

HLA-B*15:02

22 HLA type for Allopurinol SJS/TEN in SE Asians?

HLA-B*58:01

23 Enzyme deficiency causing haemolysis with primaquine?

G6PD deficiency

24 TPMT deficiency + azathioprine = ?

Severe myelosuppression

25 CYP2D6 poor metaboliser + codeine = ?

Morphine toxicity

26 CYP2C19 poor metaboliser + clopidogrel = ?

Reduced antiplatelet effect → thrombosis

27 Type B ADR — example: anaphylaxis with penicillin — what is 'B'?

Bizarre — dose-independent, unpredictable

28 Opioid withdrawal = which Rawlins-Thompson type?

Type E (End-of-use)

29 Carcinogenesis with alkylating agents = which type?

Type D (Delayed)

30 HPA axis suppression with long-term steroids = which type?

Type C (Chronic)

31 PRR stands for?

Proportional Reporting Ratio

32 BCPNN method is used by which database?

WHO VigiBase (UMC)

33 MGPS/EBGM method used by which database?

FAERS (FDA)

34 IC025 signal threshold in BCPNN?

IC025 > 0

35 EBGM05 signal threshold in MGPS?

≥ 2

36 Expedited reporting — fatal SUSAR (clinical trial)?

7 calendar days

37 Expedited — other serious unexpected SARs?

15 calendar days

38 SUSAR stands for?

Suspected Unexpected Serious Adverse Reaction

39 PSUR stands for?

Periodic Safety Update Report

40 UK spontaneous ADR reporting system?

Yellow Card (MHRA)

41 USA spontaneous ADR reporting system?

MedWatch (FDA)

42 Phase 0 uses what kind of dose?

Microdose (<1/100 of therapeutic dose)

43 Phase I trials in which population?

Healthy volunteers (20–80)

44 What is a DHPC?

Direct Healthcare Professional Communication — urgent safety message

45 Irinotecan diarrhoea/neutropaenia linked to which gene?

UGT1A1*28

46 SCORTEN predicts mortality in which condition?

SJS / TEN

47 Metformin + IV contrast → risk of?

Lactic acidosis (MALA)

48 Minimum case reports to raise a PV signal?

≥ 3 case reports

49 VigiAccess allows what?

Public access to WHO global ADR data

50 ICSR stands for?

Individual Case Safety Report

15 High-Yield Exam Facts ▾

HY-01

Naranjo Q6 is the only question where answering "No" gives a positive score (+1) — placebo did NOT cause the reaction.

HY-02

WHO-UMC vs Naranjo agreement is weak — Kappa = 0.463. They often yield different causality categories for the same case.

HY-03

Hartwig Level 6 ≠ Level 7: Level 6 = contributed to death. Level 7 = primary/direct cause of death. A very common exam trap.

HY-04

PVPI NCC = IPC Ghaziabad. CDSCO (New Delhi) is the regulatory authority, NOT the NCC. Established 2010; joined WHO PIDM 1998.

HY-05

HLA-B*57:01 → Abacavir: mandatory pre-screening. Rechallenge = potentially fatal. If positive → drug CONTRAINDICATED. (~8% Caucasians affected)

HY-06

HLA-B*15:02 → Carbamazepine SJS: South/SE Asian populations including South Indian Tamils. HLA-B*58:01 → Allopurinol SJS/TEN.

HY-07

Signal detection: BCPNN (IC025>0) = WHO/VigiBase. MGPS (EBGM05≥2) = FDA/FAERS. PRR (≥2, CI>1) = EMA/MHRA. Signal ≠ proven causality.

HY-08

Fatal SUSAR = 7 days. Other serious unexpected SARs = 15 days. PSUR = every 6 months for first 2 years post-approval.

HY-09

Schumock-Thornton: TDM not performed = Definitely Preventable (Q4). Apply AFTER confirming ADR. Assesses preventability, NOT causality.

HY-10

DoTS classification: Dose (Toxic/Collateral/Hypersusceptibility) × Time (Independent/First-dose/Intermediate/Late/Withdrawal/Long-term) × Susceptibility.

HY-11

Metformin + IV contrast: Stop Metformin 48h BEFORE contrast; restart only after renal function confirmed normal ≥48h post-procedure. MALA = Type C ADR.

HY-12

TPMT deficiency + Azathioprine/6-MP = severe myelosuppression. UGT1A1*28 + Irinotecan = severe diarrhoea and neutropaenia.

HY-13

Rawlins-Thompson Type F = Failure — often missed. OCP failure with rifampicin is the classic example. Drug interaction causing therapeutic failure.

HY-14

WHO-UMC Conditional vs Unassessable: Conditional = more data awaited (relationship not impossible). Unassessable = insufficient/contradictory — cannot be evaluated even if more data comes.

HY-15

Phase 0: Microdosing (<1/100 therapeutic dose), ~10 subjects, no therapeutic intent. Phase I = healthy volunteers, safety/PK. Phase III = pivotal RCTs for drug approval.

Quick Reference Summary

WHO-UMC orderCertain → Probable → Possible → Unlikely → Conditional → Unassessable

Naranjo scoringDefinite ≥9 · Probable 5–8 · Possible 1–4 · Doubtful ≤0 · Max=+13 · Min=−4

Hartwig severityMILD 1–2 · MODERATE 3–4 · SEVERE 5–6–7 (5=life-threat · 6=contributed to death · 7=direct cause)

Schumock-ThorntonDefinitely Preventable (≥1 of 7 criteria) → Probably Preventable → Not Preventable

Key HLAB*57:01→Abacavir · B*15:02→Carbamazepine(SJS) · B*58:01→Allopurinol(SJS/TEN)

Signal thresholdsBCPNN IC025>0 · MGPS EBGM05≥2 · PRR≥2 (CI lower bound >1)

Reporting timelinesFatal SUSAR = 7 days · Other serious unexpected = 15 days · PSUR = 6-monthly (yr 1–2)