MODULE 1: CASE INTAKE (INITIAL STEP)

What is Case Intake?

Case Intake is the first step in the Pharmacovigilance (PV) workflow where information about a potential adverse event (AE) is received, captured, and logged into the PV system. This step ensures that every safety-related report reaching the company is identified, documented, and forwarded for validation.

The purpose is to:

• Identify whether the received information is related to an adverse event
• Collect all available details from the source
• Assign a Day 0 (date when the company becomes aware of the AE)
• Generate a unique case reference number
• Transfer the case to the Case Validation step

SOURCES OF CASE INTAKE

A case may come from multiple channels such as:

• Healthcare professionals (HCPs)
• Patients/caregivers
• Call centres
• Market complaints
• Literature monitoring
• Clinical trials
• Social media (Twitter, Facebook, Instagram — if monitored)
• Company website or mobile app
• Patient support programs
• Sales representatives
• Regulatory authority reports

Minimum Criteria for a Valid Case

A valid ICSR case must have:

1. Identifiable Patient
2. Identifiable Reporter
3. Suspect Product
4. Adverse Event / Complaint

Note: If any of these four are missing → case is invalid and marked as non-valid.

WHAT A PSA DOES AT CASE INTAKE?

The PSA must:

1.      Identify if the report contains safety information

Does it describe:

• An adverse event?
• A product quality issue?
• A medication error?
• Lack of efficacy?
• Misuse/overdose?

2.      Capture all the information exactly as received: No interpretation is done here.

3.      Assign DAY 0: Day 0 = the date when anyone in the company becomes aware of the AE.

4.      Assign a case ID: Case is logged into a safety database like ArisG, Argus, or Veeva.

5.      Forward the case to Case Validation team

EXAMPLE OF CASE INTAKE:

Scenario

A patient calls the company’s medical information helpline to report an issue.

Patient’s Message

“I started taking Metformin 500 mg last week. After two days of starting the medicine, I developed severe stomach pain and loose motions. I stopped the medicine yesterday but I still feel weak.

My name is Anita Sharma. My doctor is Dr. Mehta.”

How the PSA Handles This Case

Step 1: Identify the safety information

The message contains:

• Suspect drug: Metformin 500 mg
• Adverse event: Severe stomach pain, loose motions
• Patient identifier: Name – Anita Sharma
• Reporter: Patient herself

So, it looks like a potential AE case.

Step 2: Capture the information exactly as provided

PSA records:

• Reporter name: Anita Sharma
• Reporter type: Consumer
• Drug: Metformin 500 mg
• Event: “Severe stomach pain and loose motions”
• Start date: “Last week”
• Onset date: “Two days after starting”
• Action taken: Stopped medicine yesterday
• Outcome: Not recovered / ongoing weakness

No interpretation or judgment is added.

Step 3: Assign DAY 0

If the call was received on 20 November 2025, Day 0 = 20 November 2025.

This date will influence reporting timelines later.

Step 4: Create a unique Case ID

Example: CASE-ID: IND-MET-2025-001245

This case will be processed further in the database.

Step 5: Forward the case for Case Validation

The validator will now check whether:

• It meets the minimum 4 criteria
• It is serious or non-serious
• It needs follow-up
• It needs expedited reporting

CASE INTAKE – KEY POINTS TO REMEMBER

• No interpretation or medical judgement is added
• No correction of grammar or text
• AE must be captured in verbatim
• Day 0 must be accurate
• Intake must be completed within strict timelines
• All information sources must be screened daily

MODULE 2: CASE VALIDATION

Case validation is the second step in PV workflow after case intake.
It involves checking whether the received safety information qualifies as a valid Individual Case Safety Report (ICSR) according to regulatory requirements.

Regulators such as EMA, FDA, MHRA, PMDA require four essential elements for a case to be considered valid. The validation step ensures these elements are present and confirms that the case can move to processing and reporting.

Four Minimum Criteria for a valid ICSR

A report is considered valid only if it contains all four elements:

1. Identifiable Reporter

Someone who provided the information must be identifiable.
This includes:

• Name (even initials acceptable)
• Contact details (email / phone / address)
• Qualification (HCP or non-HCP)

Examples of valid reporters:

• Dr. Rohan (HCP) reporting a side effect through email
• Patient’s relative calling a helpline
• Pharmacist reporting a suspected ADR through a portal

2. Identifiable Patient

The patient must be identifiable by at least one descriptor:

• Age or age group
• Gender
• Initials
• Patient ID number
• Date of birth
• Other unique identifiers (but NOT exact address due to privacy)

Example:

• “55-year-old female treated for hypertension.”
• “Male infant, 3 months old.”
• “Patient ID: P12456, M/45 yrs.”

3. Suspect Product

Any drug/medicine/biologic/vaccine suspected to have caused the reaction.
Minimum details needed:

• Brand name OR generic name
• Dose, route, indication (if available but not mandatory for validity)
• If multiple drugs are given, suspect drug must be clearly identifiable

Example:

• Atorvastatin 20 mg (suspect)
• COVID-19 Vaccine (suspect)

4. Adverse Event (Reaction)

At least one clinical description of an AE or a change in medical condition after drug exposure.

• Medical terminology not necessary; lay language is acceptable.
• Must indicate harm or negative outcome.

Example:

• “Patient developed severe muscle pain after starting Atorvastatin.”
• “High fever and chills after vaccination.”
• “Rash and itching within 2 hours of dose.”

WHY IS CASE VALIDATION IMPORTANT?

·         Ensures compliance with global PV regulations

·         Prevents processing of incomplete or non-reportable cases

·         Helps meet strict reporting timelines (15-day or 7-day expedited reporting)

·         Maintains data quality for signal detection & risk assessment

Note: If any of the four criteria are missing → case is considered INVALID and is kept as Non-Valid Case or Non-Case, documented for record but not processed as ICSR.

VALIDATION WORKFLOW

Step 1: Check for Completeness

The PSA checks if all 4 minimum criteria are present:

• Reporter? ✔️
• Patient? ✔️
• Suspect Drug? ✔️
• Adverse Event? ✔️

If YES → proceed to validation.
If NO → mark as "Non-valid" and follow internal process (e.g., outreach for missing information).

Step 2: Verify Reporter Identity

• Ensure the reporter is real (not anonymous).
• If unclear, PSA may contact reporter for clarification.

Example:
Email received without name → PSA sends follow-up:
“Could you please confirm your name and relationship to the patient?”

Step 3: Confirm Patient Identifiability

PSA ensures that the patient details allow distinguishing this patient from others.

Correct example:
“40-year-old male with diabetes.”

Not acceptable:
“Someone got sick after taking the drug.”

Step 4: Verify Suspect Drug Details

PSA checks:

• Was the drug taken?
• Was the drug suspected to cause the event?
• Is this drug part of the company’s product list?

Step 5: Confirm the Adverse Event

• The description must indicate harm, disability, abnormal test, or symptom.
• If unclear (“patient felt something unusual”), PSA requests more information.

Step 6: Determine Seriousness

Once valid, seriousness is assessed based on:

• Death
• Hospitalization
• Life-threatening event
• Disability
• Congenital anomaly
• Medically important event (MIE)

Seriousness determines timelines:

• Serious cases → 7 or 15-day reporting
• Non-serious cases → Periodic reporting

Step 7: Date of Awareness

Regulatory clock starts from:

• The date company FIRST becomes aware of the valid case

This determines the reporting deadline.

Step 8: Documentation & Forwarding

After successful validation:

• Case is assigned a case number
• Entered into the safety database
• Forwarded to the Case Processor

MODULE 3: SERIOUSNESS ASSESSMENT

Seriousness assessment is a key step in the PV workflow to determine whether the adverse event (AE) requires expedited reporting to regulatory authorities.
It is performed during Case Validation after confirming the minimum criteria for an ICSR.

What is Seriousness?

Seriousness refers to the regulatory definition of how severe an AE is based on clear, internationally accepted criteria.

It is NOT the same as severity.

• Severity = clinical intensity (mild/moderate/severe)
• Seriousness = regulatory impact

Example:

• Severe headache → severe but not serious
• Mild anaphylaxis managed at home → mild but serious

ICH E2A SERIOUSNESS CRITERIA

An AE is considered SERIOUS if it meets any of the following 6 criteria:

1. Death

The patient dies as a result of the AE.

Examples:

• Death due to anaphylaxis
• Sudden cardiac arrest after drug intake

2. Life-threatening

The patient was at immediate risk of death at the time of the event.

Examples:

• Severe hypotension
• Severe anaphylaxis needing resuscitation
• Ventricular arrhythmia

3. Hospitalisation (Initial or Prolonged)

Hospitalization due to the AE or AE leads to extension of existing stay.

Include:

• Emergency admission
• 24-hour observation admission

Exclude:

• Elective/planned hospitalisation

Examples:

• Drug-induced acute pancreatitis
• GI bleed requiring admission

4. Disability or Permanent Damage

AE results in lasting physical, psychological, or functional impairment.

Examples:

• Drug-induced hearing loss
• Vision impairment
• Permanent motor weakness

5. Congenital Anomaly/Birth Defect

Exposure to drug during pregnancy results in fetal abnormality.

Examples:

• Antiepileptic drug → cleft palate in new-born
• Isotretinoin exposure → birth defects

6. Required Intervention to Prevent Permanent Impairment

A medical or surgical intervention was needed to avoid permanent harm.

Examples:

• Epinephrine administered to prevent respiratory collapse
• Emergency antidote administration
• Surgery to prevent organ damage

Non-Serious Adverse Events

These do NOT meet ICH seriousness criteria.

Examples:

• Mild rash
• Headache
• Local injection site pain
• Transient dizziness

Non-serious AEs go into periodic safety reporting:

• PSUR (Periodic Safety Update Report)
• PBRER (Periodic Benefit-Risk Evaluation Report)

SERIOUSNESS VS. SEVERITY – IMPORTANT DISTINCTION

Example:

• Severe vomiting → Not serious
• Mild anaphylaxis at home → Serious (life-threatening)

EXPEDITED REPORTING TIMELINES (ICH E2A)

If a case is serious → must be reported rapidly to health authorities.

Fatal / Life-threatening

• 7 Calendar Days

Other Serious Unexpected Cases

• 15 Calendar Days

Examples of 7-day reporting cases:

• Drug-induced cardiac arrest
• Severe anaphylaxis
• Fulminant hepatic failure

Examples of 15-day reporting cases:

• Drug-induced pancreatitis
• Seizures
• Hospitalisation due to acute kidney injury

 NON-SERIOUS CASE REPORTING

Non-serious cases are not expedited.

They are included in:

• PSUR (Periodic Safety Update Report)
• PBRER (Periodic Benefit–Risk Evaluation Report)

Usually cumulative data, submitted every:

• 6 months
• 1 year
• 3 years (depending on regulatory phase)

EXAMPLES

Example 1

A 40-year-old male hospitalized for drug-induced pneumonia.

·         Serious — Hospitalisation

·         15-day report

Example 2

A patient died after a dose of chemotherapy.

·         Serious — Death

·         7-day report

Example 3

Mild vomiting after taking antibiotic.
✘ Not Serious
→ Periodic reporting only

Example 4

Pregnant woman took Drug X, delivered baby with limb deformity.

·         Serious — Congenital anomaly

·         Expedited reporting (15 days)

Example 5

Patient fainted but recovered at home, no medical visit.
Decision: Was the fainting life-threatening?
If yes → Serious
If no → Non-serious

Medical confirmation needed based on description.

RED FLAGS THAT INDICATE SERIOUSNESS

• ICU admission
• Emergency surgical intervention
• Organ failure
• Seizures
• Loss of consciousness
• Severe bleeding
• Stroke-like symptoms
• Foetal exposure with abnormal ultrasound

How PSAs Document Seriousness

A PSA must:

·         Select the seriousness criterion

·          Capture the date of outcome

·         Document clinical details clearly

·         Justify the seriousness choice

·         Determine expedited timeline

Route the case for rapid submission.

MODULE 4: CASE PROCESSING

Case Processing is the core operational activity of Pharmacovigilance.
Once a case is validated (minimum 4 criteria confirmed), it moves into processing, where the PSA enters, evaluates, codes, and prepares the case for medical and quality review.

Objectives of Case Processing

• To accurately and completely capture adverse event information in the safety database
• To ensure medical accuracy and consistency
• To prepare the case for expedited or periodic regulatory reporting
• To maintain data integrity for signal detection and risk assessment

Steps in Case Processing

Case processing typically includes the following components:

Step 1: Data Entry in Safety Database

Once a case is validated, it is entered into a safety database like:

• Argus
• ArisG
• Veeva Vault Safety
• MedDRA-supported systems

The PSA enters details in structured fields:

Data entered includes:

·         Patient demographics

·         Suspect & concomitant medications

·         Adverse event details

·         Lab reports / investigations

·         Reporter details

·         Past medical history

·         Treatment details

·         Product information

·         Reporter’s narrative

Key Principle:

“Enter exactly what the reporter says—no assumptions, no editing.”

Step 2: Chronology & Timeline Building

The PSA reconstructs the sequence of events:

1. Drug start date
2. Event onset date
3. Hospitalization dates
4. Outcome date
5. Date of last dose
6. Recovery or follow-up dates

Why it matters:

• Helps assess causality
• Determines expectedness
• Supports regulatory timelines

Step 3: Medical Coding (Standardization)

Terminologies must be standardized to support global consistency.

(A) MedDRA Coding for Adverse Events

Using MedDRA hierarchy:

• LLT (Lowest Level Term)
• PT (Preferred Term)
• HLT
• SOC

Example:
“Severe stomach pain” → LLT (Abdominal pain) → PT: Abdominal Pain

Rules:

·         Code what is reported

·         Avoid interpreting or diagnosing

·         Do not code severity or seriousness

(B) WHO-DD Coding for Drugs

Used for:

• Suspect drugs
• Concomitant medications
• Indications

Ensures standardized drug names.

Step 4: Causality Assessment

Determines whether drug caused the event.

Most common tools:

• WHO-UMC causality scale
• Naranjo algorithm
• Manufacturer’s internal guidance
• Clinical judgment by medical reviewer

Categories:

• Certain
• Probable
• Possible
• Unlikely
• Unassessable

Factors assessed:

·         Temporal relationship

·         Dechallenge / Rechallenge

·         Known pharmacology

·         Alternative causes

·         Drug-drug interactions

Step 5: Expectedness Assessment

Determines whether the AE is mentioned in:

• Investigator’s Brochure (IB) — Clinical trials
• Company Core Data Sheet (CCDS) — Post-marketing
• Product Label / SmPC / PI

Classification:

• Expected (Listed)
• Unexpected (Unlisted)

Use:

• Determines 15-day reporting for Serious Unexpected cases

Step 6: Narrative Writing

The narrative is the complete medical story of the case.

Should include:

·         Patient details

·         Drug details (suspect and concomitant)

·         Full chronology

·         AE details

·         Seriousness criteria

·         Relevant medical history

·         Lab reports

·         Reporter’s statements

·         Treatment given

·         Outcome

Golden rule:

Clear, concise, chronological, medically accurate.

Step 7: Follow-up Request (If Needed)

Follow-up needed when:

• Missing minimum criteria
• Missing dates
• Incomplete drug information
• Seriousness unclear
• Outcome missing
• Pregnancy cases
• Lack of essential labs

Requests are sent via:

• Email
• Call
• Safety query letters
• Medical information teams

Step 8: Medical Review

Performed by:

• Physician
• Medical Safety Officer
• Pharmacovigilance Scientist

They review:

·         Coding accuracy

·         Causality

·         Expectedness

·         Narrative quality

·         Seriousness classification

·         Completeness

Their sign-off is necessary for regulatory submission.

Step 9: Quality Review (QA Check)

QA ensures:

• Accuracy
• Consistency
• Alignment with SOPs & regulatory guidelines
• Formatting correctness

Audit trail must be maintained.

Step 10: Regulatory Submission

Based on seriousness & expectedness:

Serious Unexpected → 15-Day Report

Fatal/Life-threatening → 7-Day Report

Non-serious → PSUR/PBRER

Cases are transmitted via:

• E2B (R2 or R3) XML
• Gateway submission
• National portals (FDA, EMA, MHRA, PVPI etc.)

Case Processing Workflow

Intake → Validation → Data Entry → Coding → Causality → Expectedness → Narrative → QA → Medical Review → Submission

Important Tips for PSAs

• Never assume missing information
• Use exact reporter words
• Always check chronology
• Run consistency checks
• Ensure seriousness criteria match narrative
• Validate MedDRA codes carefully
• Maintain clean, professional narrative style

Example of Case Processing

Reporter says:
“Patient took Amoxicillin for 3 days and developed rash and fever. Stopped drug on Day 4. Rash improved.”

What the PSA does:

✔ Validate case → Yes (all 4 criteria present)
✔ Enter demographics
✔ Enter suspect drug + start/stop dates
✔ Enter AE onset date
✔ MedDRA code “Rash” and “Pyrexia”
✔ Assess seriousness → Non-serious
✔ Causality → Probable (temporal relation + dechallenge)
✔ Expectedness → Expected
✔ Write narrative
✔ Send for QA and Medical review
✔ Submit case as part of periodic reporting

MODULE 5: DATA CODING

Data coding is the process of standardizing all medical and drug-related information in a safety case using internationally accepted dictionaries. This ensures uniformity across all cases and enables accurate signal detection, regulatory reporting, and data analysis.

Data coding occurs after case registration and before narrative writing.

A. Why Coding is Needed

• To ensure consistency across global databases
• To allow system-based search and signal detection
• To avoid ambiguity from free-text entries
• To ensure regulatory compliance
• To make global safety reports uniform across all regions

B. What All Items Are Coded?

1. Adverse Events / Reactions
2. Indications
3. Medical History
4. Past Drug History
5. Concomitant Medications
6. Laboratory Tests (sometimes)

C. Coding Dictionaries Used

1. MedDRA (Medical Dictionary for Regulatory Activities)

Used for:

• Adverse events
• Indications
• Medical history
• Procedures
• Investigations

MedDRA Hierarchy Levels:

1. SOC (System Organ Class) – Highest level
2. HLGT (High-Level Group Term)
3. HLT (High-Level Term)
4. PT (Preferred Term) – Main coding term
5. LLT (Lowest Level Term) – Selected term for coding

Example:
Free text: “Patient had swelling of face”
Code:

• LLT: Facial swelling
• PT: Oedema of face

2. WHO Drug Dictionary (WHODD)

Used for:

• Suspect drugs
• Concomitant medications
• Past medications
• ATC classification

Key Components:

• Drug Name – brand or generic
• Preferred Base Name (PBN) – core active ingredients
• ATC Code – classification of drug’s pharmacologic group
• DDI (Drug Dictionary Identifier)

Example:
Free text: “Tab Paracetamol 500 mg”
Coding in WHODD:

• PBN: Paracetamol
• ATC: N02BE01

D. How Coding is Performed (Step-by-Step)

1. Read the source document thoroughly

• Extract all medical terms exactly as written.
• Avoid assumptions or interpretations.

2. Match the term to the most appropriate LLT

• Use the MedDRA browser or internal dictionary.
• Select the LLT, but the case will map to the PT automatically.

3. Ensure medical accuracy

• Do not code signs/symptoms separately if a diagnosis is provided.
• Example: If diagnosis is “Pneumonia,” do not code “fever,” “cough,” etc.

4. Code based on the reporter’s verbatim

• No medical interpretation unless allowed by SOP.

5. Avoid vague or generalized terms

Incorrect: “Bad reaction” → too vague
Correct: Identify exact symptoms from the narrative.

6. Code drugs using WHO Drug

• Match strength, dose form (tablet, injection), combination drugs.
• Add ATC codes.

7. Review coded terms

• Ensure:
• No duplications
• No contradictions
• All relevant terms are captured
• Primary suspect drug is correctly marked

E. What Should NOT Be Coded

• Social history (unless medically relevant)
• Reporter’s comments unless containing medical information
• Administrative information (dates, identifiers)
• Duplicate medical terms

F. Examples of Correct Coding

Example 1

Free text: “Patient developed severe itching and red patches after taking amoxicillin.”
Coding:

• LLT: Pruritus
• LLT: Erythema
  WHODD:
• Amoxicillin → ATC: J01CA04

Example 2

Free text: “Past history of diabetes mellitus type 2.”
Coding:

• LLT: Type 2 diabetes mellitus

Example 3

Free text: “Patient was prescribed Ibuprofen 400 mg for pain.”
Coding:

• Ibuprofen → ATC: M01AE01

G. Quality Checks in Coding

• Is the LLT the closest match?
• Is the PT medically meaningful?
• Are all relevant terms coded?
• Is the drug-role classification correct?
• Suspect
• Concomitant
• Interacting
• Is the preferred term aligned with narrative and medical review?

MODULE 6: CAUSALITY ASSESSMENT

Causality assessment is the clinical step in pharmacovigilance where a medically-qualified reviewer (or a multidisciplinary team for complex cases) evaluates whether the suspected medicine is likely to have caused the adverse event (AE). The outcome influences regulatory reporting, labeling, signal detection, and clinical follow-up. Below I cover purpose, principles, common methods, a step-by-step approach, examples, documentation, pitfalls, and best practices.

1) Purpose — why we do causality assessment

• Decide whether an event is possibly, probably, or unlikely related to a drug.
• Determine whether the case needs expedited regulatory reporting (e.g., SUSAR: serious, unexpected, and suspected causal relationship).
• Inform medical management (stop drug, supportive care, rechallenge decisions).
• Support signal detection and safety surveillance.
• Provide a transparent clinical rationale that can be audited.

2) Key principles and inputs used

Causality is not purely algorithmic — it’s a clinical judgement supported by evidence. Typical inputs:

• Temporal relationship: time from drug start (or dose change) to AE onset.
• Dechallenge: improvement when drug withdrawn.
• Rechallenge: recurrence on re-exposure (strong evidence if ethical/available).
• Plausibility: pharmacology, known ADR profile, class effects.
• Alternative explanations: underlying disease, other medications, infections, lab abnormalities.
• Dose–response: AE related to dose or accumulation.
• Objective data: labs, biopsy, ECG, imaging.
• Previous reports: literature, company safety database, spontaneous reporting systems.
• Quality of information: completeness and reliability of the case.

3) Common structured methods / scales

These are tools to make the process consistent. They differ in design and use case.

A. WHO-UMC System (widely used in regulatory context)

Categories: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, Unassessable/Unclassifiable.
Relies on temporal relationship, dechallenge/rechallenge, alternative causes, and prior knowledge.

B. Naranjo Algorithm (questionnaire with score)

A scored checklist (e.g., +2 for previous conclusive reports, +1 for temporal relationship, etc.). Common in clinical research but less used for regulatory spontaneous reports because it can over-simplify.

C. Specialized algorithms

• RUCAM for drug-induced liver injury (DILI).
• Liverpool ADR Causality Assessment Tool for certain complex ADRs.

D. Company/Regulatory Algorithms

Many sponsors create SOP-aligned causality templates combining clinical narrative plus a chosen method (often WHO-UMC) for consistency.

4) Step-by-step practical approach (how a medical reviewer should proceed)

Step A — Review the case source documents

• Read all source documents (HCP notes, discharge summary, lab reports, autopsy, ECG, concomitant meds).
• Confirm completeness of key data: onset date/time, drug start/stop dates, dose, dechallenge/rechallenge details.

Step B — Establish temporality

• Can the timing support causation?
• Example windows: minutes–hours for anaphylaxis, days–weeks for rash, weeks–months for some organ toxicities.
• If timing is implausible → probably unlikely.

Step C — Exclude alternative causes

• Look for infections, new diagnoses, disease progression, interactions, overdose, contaminants.
• Consider co-medications that are known causes.

Step D — Examine dechallenge / rechallenge

• Positive dechallenge (improvement after stopping) supports causality.
• Rechallenge with recurrence is strong evidence — but rarely done intentionally.

Step E — Assess biological plausibility and prior knowledge

• Is the AE listed in the product label or prior literature? Is there a known mechanism?
• If unexpected but biologically plausible, it may be “possible” or “probable” depending on other evidence.

Step F — Consider objective data & lab tests

• Abnormal LFTs, eosinophilia, autoantibodies, ECG changes, biopsy results all add weight.

Step G — Decide on category & document rationale

• Use your chosen method (e.g., WHO-UMC) and write a concise justification: facts and reasoning. Avoid vague statements.

5) WHO-UMC categories — how to interpret them (practical cues)

• Certain
• Time relationship plausible.
• Cannot be explained by disease/other drugs.
• Response to withdrawal plausible.
• Definitive pharmacology or objective evidence (lab) or positive rechallenge.
• Probable / Likely
• Reasonable time relationship.
• Unlikely to be explained by other causes.
• Reasonable response to dechallenge.
• Rechallenge not required.
• Possible
• Time relationship reasonable but could also be explained by disease or other drugs.
• Information may be inadequate for stronger assignment.
• Unlikely
• Temporal relationship makes causal link improbable.
• Other explanations more likely.
• Conditional / Unclassified
• Event requires more data before assessment (pending follow-up).
• Unassessable / Unclassifiable
• Insufficient or contradictory information; cannot be judged.

6) Example case (walk through)

Case: 45-yr-old female started Drug A for hypertension on April 1. On April 5 she developed generalized itchy rash and facial swelling; presented to ER on April 6. She stopped Drug A on April 6; symptoms resolved over 3 days after antihistamines. No new infections, no other new meds. She had previously tolerated Drug B (another antihypertensive).

Assessment:

• Temporality: onset 4 days after starting — plausible for hypersensitivity.
• Dechallenge: improvement after stopping → supportive.
• Alternative causes: none identified.
• Prior knowledge: Drug A known to cause hypersensitivity rash (label).
• Rechallenge: not performed (unnecessary / unethical).

WHO-UMC assignment: Probable/Likely.
Documentation: state dates, timeline, dechallenge response, absence of alternative causes, relevant literature/label citation, final category with rationale.

7) Documentation & record-keeping (what to include)

• Final causality category and method used (e.g., WHO-UMC).
• Short written justification: key facts (dates, dechallenge/rechallenge, labs, alternative causes).
• Name and designation of assessor and date of assessment.
• Any differing opinions (if multidisciplinary review).
• If changed later (after follow-up): document the reason and date.

A typical causality note:

“WHO-UMC: Probable. AE onset 4 days after starting Drug A (2025-04-05). Symptoms improved within 3 days of stopping drug (2025-04-09). No alternative causes identified; drug labeled for hypersensitivity. Assessed by Dr. X on 2025-04-12.”

8) Regulatory implications

• If you assign suspected causality for a serious AND unexpected event → expedited reporting (SUSAR) in many jurisdictions.
• If causality is unlikely, may not require expedited submission but still retained in the safety database for aggregate review.

9) Special situations & nuances

• Multiple suspect drugs: assess each drug separately; consider interactions or additive effects.
• Class effects: if the drug is similar to others known to cause the AE, that strengthens plausibility.
• Vaccines & immune events: timelines and biologic plausibility differ (e.g., immune thrombocytopenia).
• Pregnancy exposures: consider maternal vs foetal events and timing of exposure.
• Overdose / toxicity vs idiosyncratic reactions: dose–response supports causality in toxicity; idiosyncratic reactions may occur at therapeutic dose.
• Insufficient information: mark Conditional/Unclassified and request follow-up.

10) Common pitfalls to avoid

• Over-reliance on algorithm scores without clinical review.
• Ignoring alternative explanations (e.g., underlying disease).
• Using rechallenge data when rechallenge was done inadvertently but without controls — interpret cautiously.
• Coding a causality based only on temporal association (post hoc = not necessarily causal).
• Failing to update causality after receiving follow-up data.

11) QA, training, and SOPs

• Organizations should define which causality method is standard (WHO-UMC common for regulatory reporting).
• Implement peer review or consensus for borderline/serious cases.
• Train medical reviewers with case examples and inter-rater reliability exercises.
• Periodically audit causality assessments for consistency and quality.

12) Quick checklist for the assessor

1. Are start/stop/onset dates present and clear?
2. Is the temporal relationship plausible?
3. Any dechallenge / rechallenge data?
4. Are objective tests supportive?
5. Alternative causes considered & documented?
6. Is there prior information in literature/label?
7. Which causality method used? (state clearly)
8. Final category with succinct rationale recorded.
9. Assessor details and date.

13) Short reference table

MODULE 7: EXPECTEDNESS

Expectedness determines whether an adverse event (or adverse reaction) is listed in the product’s reference safety information (RSI). It answers the question: Is this adverse reaction already known (expected) for this medicine/vaccine/biologic, or is it new/unlisted (unexpected)?

• Expected = event (by term, nature, severity, or frequency) appears in the RSI (e.g., Investigator Brochure (IB) for clinical trials; SmPC/label/Core Data Sheet/CDS for marketed products).
• Unexpected = event is not described in the RSI (or is described but differs materially in nature or severity), and therefore is considered new safety information.

Expectedness is assessed after you have: (a) established an adverse event/reaction and (b) completed causality/suspect-drug assessment (i.e., the event is considered suspected to be related to the drug). For regulatory expedited reporting (e.g., SUSARs), the event must be serious, suspected causal, and unexpected.

Why it matters

• Regulatory reporting: Unexpected serious suspected adverse reactions (SUSARs) often require expedited reporting to regulators and ethics committees (eg, 7-/15-day timelines in many regions).
• Labeling & risk management: Unexpected events can trigger label updates, risk minimization measures, or safety signal investigations.
• Signal detection: Unexpectedness helps prioritize cases for signal review and aggregate evaluations.
• Audit & compliance: Expectedness assessments must be defensible and well-documented.

Reference Safety Information (RSI) — where to compare

• Clinical trials: Investigator Brochure (IB) — usually the core RSI. For marketed products studied in trials, the SmPC (or local label) may be used if agreed in the protocol/SOP.
• Post-marketing: SmPC / Package Insert / Product Label or Core Data Sheet (CDS).
• Vaccines / biologicals: Product label + specific vaccine safety guidance; for novel products, the IB or manufacturer’s Investigator Safety Information.
• Combination products / generics / off-label use: use the RSI agreed for that study or region (e.g., sponsor CDS, not an unrelated label).

Always use the most current approved RSI version applicable to the jurisdiction and trial/protocol.

Principles for Expectedness Assessment

1. Compare the adverse reaction (PT / LLT) against the RSI — exactness matters. Use MedDRA Preferred Term (PT) mapping.
2. Severity and nature: an AE may be listed in RSI, but the severity or specific presentation may be more serious than the RSI description — that can make it “unexpected” (e.g., “mild rash” listed vs “Stevens-Johnson syndrome” observed).
3. Causality prerequisite: expectedness usually applies only if the event is suspected to be related to the drug. If causality is ‘unlikely’, expectedness is irrelevant for SUSAR logic.
4. New clinically important information: even if a PT is listed, a new frequency, unusual presentation, or new severity may be considered unexpected in regulatory terms.
5. Source of truth: RSI documents are the authoritative source. If multiple RSIs exist (IB vs SmPC), follow the protocol/SOP on which to use. Document the chosen RSI and version/date.

Step-by-step workflow (operational)

1) Prepare the case for expectedness check

• Confirm coding of the AE(s) using MedDRA PTs (and LLTs if needed).
• Confirm causality assessment: is the event classified as suspect (related) to the medicinal product?

2) Select the correct RSI

• For trials: IB (include version/date). If protocol mandated SmPC, use that.
• For marketed cases: current SmPC/label/CDS for the country/region or the sponsor’s global CDS as per SOP.
• Record RSI version/date in the case.

3) Search RSI for the PT and synonyms

• Search for the PT and likely synonyms; check SOC/HLT if RSI uses broad language.
• Use MedDRA mapping: does an LLT/PT in the case map to a PT phrasing included in the RSI?

4) Assess match quality

• Direct match: PT appears verbatim or as an explicit expected reaction → Expected.
• Close match: PT is similar or within a broader term listed (e.g., ‘peripheral neuropathy’ listed, case is ‘sensory neuropathy’) → treat as Expected if medically encompassed.
• Not listed: PT or clinical presentation not present or not encompassed by RSI → Unexpected.

5) Consider severity & clinical character

• If PT is listed but the severity or clinical pattern is materially different (e.g., listed as mild, observed as life-threatening), consider it Unexpected for reporting. Document rationale.

6) Document decision & rationale

• Capture: RSI source (name + version + date), MedDRA PT/LLT used, search evidence, final expectedness decision, assessor name/date, and rationale (short factual sentence).
• If decision affects reporting (SUSAR), trigger the regulatory reporting workflow immediately.

Examples (practical)

Example A — Clinical trial

• Case: MedDRA PT Anaphylactic shock after dose.
• RSI: IB lists Anaphylaxis as a known, rare risk.
• Outcome: Expected (term present). If serious and related → SUSAR? No for unexpectedness, but still report as serious AE per procedures (may or may not be expedited depending on causality).

Example B — Clinical trial

• Case: Acute liver failure (life-threatening).
• RSI: IB lists transaminitis and asymptomatic ALT elevation but not acute liver failure.
• Outcome: Unexpected (severity/presentation not covered). If related → SUSAR → expedited reporting.

Example C — Post-marketing

• Case: Deep vein thrombosis (DVT) reported for a contraceptive. SmPC lists thromboembolic events generally.
• Outcome: Expected (if DVT falls within “thromboembolic events”); rationale should note where in SmPC it’s referenced.

Example D — New clinical pattern

• Case: Peripheral neuropathy presenting with small-fiber neuropathy (autonomic features). RSI lists “peripheral neuropathy” historically as sensory neuropathy only.
• Outcome: potentially Unexpected (new clinical pattern). Document justification and consider regulatory notification.

Regulatory implications & timelines (high-level)

• Clinical trials: Serious, suspected, unexpected adverse reaction (SUSAR) → expedited reporting to Competent Authorities and Ethics Committees per regional timelines (examples commonly used: 7 days for fatal/life-threatening SUSARs with 8 days follow-up, 15 days for other SUSARs). (Check your local regulations and protocol; SOP should state the applicable timelines and references.)
• Post-marketing: Unexpected serious ADRs generally must be reported to regulators according to the country’s pharmacovigilance regulations and in periodic safety reports (PSUR/PBRER). Unexpected non-serious ADRs are handled per local rules (often via periodic aggregate reporting).
• Label updates: Accumulation of unexpected events may trigger safety signal procedures and label/PI updates.

Note: Because country/regional specifics vary, always reference the local regulatory requirement in your SOP (and record date/version of the rule used).

Documentation template (fields to capture)

You can paste this into your database or case form:

• Case ID:
• AE MedDRA LLT / PT:
• Verbatim term:
• Date of onset:
• Suspect product(s): (name, batch if relevant)
• Causality: (method + category)
• RSI used (document name): (e.g., IB v3.2; SmPC India v2025-01-10)
• RSI version / date:
• RSI excerpt / location (page/section):
• Expectedness decision: (Expected / Unexpected)
• Rationale: (1–2 sentence factual rationale)
• Assessor name & designation:
• Assessor date:
• If Unexpected & Serious → Regulatory action triggered? (Yes/No; detail)
• Follow-up required: (Yes/No; what & by when)

Sample SOP paragraph (copy-paste ready)

Expectedness Assessment — SOP except:

For each case with a suspected causal relationship to the investigational product, the designated safety assessor will determine expectedness by comparing the MedDRA-coded PT/LLT to the Reference Safety Information (RSI) identified for the study/region (e.g., Investigator Brochure v[version] dated [date] or SmPC dated [date]). The RSI version used must be recorded in the case. If the PT (or an encompassing higher-level term) and its severity/presentation are listed in the RSI, classify the event as Expected. If not listed, or if the observed clinical presentation/severity materially exceeds the RSI description, classify as Unexpected. The assessor will document the rationale, their name and date. For serious + suspected + unexpected events, the expedited reporting workflow must be initiated immediately per regulatory timelines.

Example wording for the expectedness justification

• “Expected — PT ‘Dizziness’ appears under ‘Nervous System Disorders’ in IB v2.1 (page 38); RSI lists ‘dizziness’ as an adverse reaction. Assessed by Dr. X on 2025-11-27.”
• “Unexpected — PT ‘Acute hepatic failure’ not present in IB v4.0 (most recent), which lists mild transaminase elevations only. Clinical course and labs consistent with acute hepatic failure. Assessed by Dr. X on 2025-11-27. Regulatory reporting initiated.”

Special scenarios & nuance

• Multiple RSIs available: follow protocol/SOP on precedence (e.g., trial protocol may require SmPC for marketed comparators). Document which RSI you used.
• Class effects: If RSI for a drug class includes a reaction, but the specific product ‘s RSI does not, discuss with medical lead/legal/regulatory—could be treated as unexpected for that product.
• Combination products: check RSI for each active ingredient and the combination product.
• Off-label use / overdose / medication error: expectedness is judged against RSI for the exposure actually used (dose/route). An overdose reaction could be unexpected compared with labelled therapeutic use.
• Limited RSI (e.g., new biologic, early phase): IB may be sparse—assess conservatively and consult sponsor medical lead if unsure.
• Non-drug causes with suspected relation: If causality strong but RSI absence is due to different cause, document clearly.

Common pitfalls & how to avoid them

• Pitfall: Using an outdated RSI.
  Fix: Always capture RSI version/date; SOP to check for latest approved RSI.
• Pitfall: Basing expectedness only on free-text search (miss synonyms).
  Fix: Use MedDRA mapping; search for synonyms and HLT/SOC terms.
• Pitfall: Ignoring severity/pattern differences.
  Fix: Include severity in assessment decision and document why a listed PT may still be unexpected.
• Pitfall: Expectedness decided before causality.
  Fix: Only determine expectedness for events judged as suspected (related).
• Pitfall: Poor documentation of rationale.
  Fix: Use the template wording above and include page/section of RSI.

Quick checklist to copy into your process

1. Has the AE been coded to MedDRA PT?
2. Is the event judged as suspected (causality not ‘unlikely’)?
3. Which RSI is applicable? (document name/version/date)
4. Does the PT (or encompassing term) appear in the RSI? (Yes/No)
5. Does the observed severity/pattern differ materially from RSI? (Yes/No)
6. Final expectedness: Expected / Unexpected.
7. Rationale recorded (1–2 lines).
8. Assessor name & date saved.
9. If Serious + Suspected + Unexpected → trigger expedited reporting.
10. Update case record and file RSI excerpt.

MODULE 8: NARRATIVE WRITING

Narrative writing is one of the most crucial steps in case processing. It is the story of the adverse event (AE) — a continuous, medically coherent summary of what happened to the patient, presented in chronological order.

It must allow any reviewer (regulator, QA, auditor, medical monitor, sponsor) to understand the case without reading the source documents.

Purpose of Narrative Writing

The narrative aims to:

• Present a clear, concise, chronological medical story
• Explain:
• What happened
• When it happened
• Why it happened (temporal relationship)
• How severe it was
• What treatment was given
• What the final outcome is
• Provide medically meaningful context for expectedness and causality assessment.

🧩 Components of a High-Quality Narrative

A good narrative generally includes the following:

1.      Patient Information

• Age, gender, or age group
• Relevant medical history
• Past or current medical conditions
• Concomitant medications
• Relevant social history (smoking/alcohol, if medically relevant)

Example:
"The patient was a 54-year-old male with a history of hypertension and type 2 diabetes."

2.      Suspect Drug Information

For each suspect product:

• Name (brand & generic)
• Formulation
• Dose, route, and frequency
• Indication for use
• Start and stop dates
• Batch/lot number (if available)

Example:
"The patient began treatment with Metformin 500 mg orally twice daily for diabetes on 12-Jan-2024."

3.      Concomitant Medication Information

Include only those relevant to the medical context:

• Drug name
• Dose
• Indication

4.      Event Description — THE CORE OF THE NARRATIVE

This is the chronological story:

🔸 Start with onset of the event

• Date of onset
• Symptoms
• Clinical findings
• Patient-reported or medically confirmed?
• How was the event discovered?

🔸 Details of the clinical course

• Progression, worsening, or improvement
• Treatments given (hospitalization, ER visits, medicines)
• Laboratory tests or diagnostic results
• Vital signs
• Physician interventions

🔸 Outcome

• Recovered, recovering, not recovered, fatal, unknown
• Date of outcome if known

Example:
"On 20-Jan-2024, after two weeks of Metformin therapy, the patient developed severe abdominal pain and vomiting. The patient visited the emergency department, where metabolic acidosis was noted (pH 7.2). Metformin was discontinued the same day. The patient was admitted and treated with IV fluids. Symptoms improved gradually, and the patient was discharged on 23-Jan-2024."

5.      Relevant Labs/Tests

Include medically meaningful results only:

• CBC, LFT, RFT
• Imaging findings (CT/MRI/X-ray)
• Any diagnostic confirmation

6.      Dechallenge and Rechallenge

Dechallenge

What happened when the drug was stopped?

• Positive → Event improved after stopping
• Negative → No improvement
• Not applicable → Drug not stopped

Rechallenge

What happened if the drug was restarted?

• Positive → Event recurred
• Negative → No recurrence
• Not done

7.      Causality Assessment Summary

This section integrates:

• Temporal association
• Biological plausibility
• Confounders
• Dechallenge/rechallenge results

Written as:

• Related / Possibly related / Unlikely related / Not related

8.      Case Closure Summary

1–2 lines summarizing the case:

• "A serious unexpected case of XXX possibly related to YYY in a patient with Z medical history."

Example of a Well-Written Narrative (Short Version)

“The case involves a 54-year-old male with hypertension and diabetes who started Metformin 500 mg orally twice daily on 12-Jan-2024. On 20-Jan-2024, he developed severe abdominal pain and vomiting and presented to the ER. Investigations revealed metabolic acidosis (pH 7.2), suggesting possible Metformin-associated lactic acidosis (MALA). Metformin was discontinued the same day. He was hospitalized and treated with IV fluids. Symptoms resolved, and he was discharged on 23-Jan-2024. A positive dechallenge was noted. No rechallenge was performed. Based on temporal association and improvement after stopping the drug, the event was assessed as possibly related to Metformin.”

Best Practices for Narrative Writing

✔ Maintain chronological order
✔ Stick to medically relevant details only
✔ Avoid assumptions or personal judgment
✔ Ensure consistency with:

• Case form fields
• Medical coding
• CIOMS standards

✔ Use third-person, past tense
✔ Avoid copying from source verbatim—summarize clearly

Simple AE Narrative – Sample Case

Patient Information:

This case concerns a 32-year-old female (weight and height not reported) with no significant past medical history. No allergies or relevant family history were reported. No concomitant medications were in use at the time of the event.

Suspect Product Information:

The patient self-initiated treatment with Ibuprofen 400 mg, orally, as needed, for headache on 05-Aug-2024. Batch/lot number and expiry date were not provided.

Event Description:

On 05-Aug-2024, approximately one hour after taking a single 400 mg dose of Ibuprofen, the patient experienced mild gastric discomfort characterized by abdominal pain and a burning sensation in the upper abdomen. The event was non-serious, self-limited, and did not require medical intervention or hospitalization.
The patient did not seek medical consultation; however, she discontinued Ibuprofen on the same day. The symptoms resolved spontaneously within a few hours.

Relevant Tests/Laboratory Data:

No laboratory investigations or diagnostic tests were performed.

Dechallenge/Rechallenge:

A positive dechallenge was observed, as symptoms resolved after discontinuation of the suspect product. Rechallenge was not attempted.

Outcome:

The patient fully recovered on the same day (05-Aug-2024).

Causality Assessment:

Based on the temporal association, known pharmacological effects of NSAIDs, and positive dechallenge, the event of gastric discomfort was assessed as related to Ibuprofen.

Case Summary:

This is a non-serious spontaneous case of gastric discomfort associated with Ibuprofen use in a 32-year-old female, resolving spontaneously following drug discontinuation.

Serious AE Narrative – Sample Case (Hospitalization)

Patient Information:

The case involves a 58-year-old male (weight and height not reported) with a medical history significant for type 2 diabetes mellitus and hypertension. Past surgical history, allergies, and family history were not reported. Concomitant medications included Amlodipine 5 mg once daily for hypertension and Metformin 1000 mg twice daily for diabetes.

Suspect Product Information:

The patient started Amoxicillin–Clavulanic Acid 625 mg, orally twice daily, for acute sinusitis on 10-Sep-2024. Batch/lot number and expiry details were not provided.

Event Description:

On 11-Sep-2024 (one day after starting therapy), the patient developed generalized itching, followed by rapid-onset swelling of the lips and eyelids and shortness of breath within minutes. Emergency medical services were contacted, and the patient was transported to the hospital. Upon arrival, he was diagnosed with acute anaphylaxis based on clinical presentation, including:

• Facial angioedema
• Wheezing
• Hypotension (BP 86/54 mmHg)
• Urticaria over the trunk

The patient was immediately treated with intramuscular epinephrine, IV antihistamines, and IV corticosteroids. Amoxicillin–Clavulanic Acid was discontinued upon admission. He was monitored in the emergency department and subsequently admitted for observation for 24 hours.

Symptoms improved significantly over the next several hours. The swelling and breathing difficulty resolved completely by 12-Sep-2024, and the patient was discharged in stable condition.

Relevant Laboratory/Diagnostic Data:

No specific allergy testing or laboratory results were provided. Diagnosis was clinical, based on signs and symptoms.

Dechallenge/Rechallenge:

A positive dechallenge was noted, as symptoms resolved following discontinuation of the suspect drug and receipt of appropriate treatment.
Rechallenge was not performed, due to the nature of the reaction (life-threatening hypersensitivity).

Outcome:

Recovered on 12-Sep-2024.

Causality Assessment:

Considering the rapid temporal association, clinical presentation typical of β-lactam allergy, absence of alternative explanations, and positive dechallenge, the event of anaphylaxis was assessed as related to Amoxicillin–Clavulanic Acid.

Case Summary:

This is a serious spontaneous case of drug-induced anaphylaxis requiring hospitalization in a 58-year-old male following administration of Amoxicillin–Clavulanic Acid for sinusitis. The event resolved after drug discontinuation and appropriate medical management.

MODULE 9: MEDICAL REVIEW

Medical Review is the clinical evaluation of an adverse event (AE) case before it is submitted to regulatory authorities. It ensures that the case is scientifically accurate, medically sound, and compliant with regulations.

Who Performs Medical Review?

Medical Review is conducted by qualified medical and safety professionals, typically:

• Physician / Medical Doctor (MD)

• Provides expert clinical judgement
• Evaluates the logical medical relationship between drug and event

• Medical Safety Officer (MSO)

• Ensures the case aligns with company safety strategy
• Identifies potential signals or trends

• Pharmacovigilance Scientist / Safety Reviewer

• Performs medical analysis along with data accuracy checks
• Supports physician with evidence and documentation

2. Key Elements Reviewed During Medical Review

The medical reviewer thoroughly evaluates various scientific and regulatory components of the case:

A. Coding Accuracy

• Ensures MedDRA terms (PT, LLT) are correctly selected
• Ensures WHO-DD coding is correct for drug names/indications
• Verifies that coding represents the true clinical situation

Example:
“Swelling of lips” should be coded as “Lip swelling” (PT), not “Angioedema” unless clinically diagnosed.

B. Causality Assessment

The medical reviewer determines whether the drug likely caused the AE.

Common causality tools:

• WHO-UMC scale
• Naranjo’s scale
• Company-specific causality criteria

They consider:

• Temporal relationship
• Dechallenge/rechallenge
• Biological plausibility
• Known side effect profile
• Concomitant medications
• Underlying disease

C. Expectedness Assessment

Reviewer determines whether the AE is:

• Expected (listed in Product Information / Investigator Brochure)
• Unexpected (not listed → potential SUSAR in clinical trials)

Expectedness determines:

·         Expedited reporting timelines

·         Whether the event qualifies as a SUSAR

D. Narrative Quality

The reviewer ensures the narrative is:

• Clear
• Chronological
• Complete
• Clinically meaningful
• Free of speculation
• Contains all details on AE onset, drug history, relevant tests, outcomes, etc.

A good narrative must allow a regulator to understand the full medical picture without reading other sections.

E. Seriousness Classification

The reviewer checks whether seriousness is correctly assigned based on ICH criteria:

• Death
• Life-threatening
• Hospitalisation
• Disability
• Congenital anomaly
• Medically important condition

Incorrect seriousness can lead to incorrect reporting timelines, so accuracy is crucial.

F. Completeness Check

Ensures all minimum and essential data are present:

Minimum 4 criteria:

1. Identifiable patient
2. Identifiable reporter
3. Suspect drug
4. Adverse event

Additional essential data:

• Lab results
• Relevant medical history
• Treatment details
• Lot/batch numbers (if required)
• Concomitant medications

Reviewer may request follow-up information before sign-off.

3. Output of Medical Review

After review, the medical reviewer:

·         Confirms medical accuracy

·         Signs off (electronically in the safety database)

·         Approves case for regulatory submission

Medical review sign-off is mandatory for:

• ICSR Regulatory Submission (VAERS, EudraVigilance, FDA)
• SUSAR reporting in clinical trials
• Aggregate reports (DSUR, PBRER)

4. Importance of Medical Review

Medical Review ensures:

• Clinical validity
• Regulatory compliance
• Prevention of misreporting
• Swift identification of safety signals
• Patient safety protection

It is the final gate before a case leaves the company.

5. Example Case for Medical Review

Case:
A 54-year-old male taking Drug X developed “high fever and rash” on Day 3.
He visited a hospital and received treatment.
Drug withdrawn → patient improved (positive dechallenge).

Medical Reviewer conclusions:

• AE coding:
  PT: “Drug eruption”
• Seriousness: Hospitalisation = Serious
• Causality: Probable
• Expectedness: Unexpected (not listed in SmPC)
• Reporting: 15-day expedited report
• Narrative: Must include timeline and dechallenge

MODULE 10: QUALITY REVIEW (SECOND-LEVEL REVIEW)

Quality Review (often called QA Check or Case Quality Review) is the final internal verification step before an Individual Case Safety Report (ICSR) is submitted to regulatory authorities. The purpose is to ensure the case is accurate, consistent, compliant, complete, and audit-ready.

1. Purpose of Quality Review

QA review ensures that the case file:

·         Reflects accurate medical and administrative information

·         Follows all PV Standard Operating Procedures (SOPs)

·         Meets global regulatory requirements (ICH, EMA, FDA)

·         Is consistent across all sections of the case

·         Is complete and ready for submission

It acts as the final checkpoint for quality and compliance.

2. What QA Ensures

A. Accuracy

QA verifies that all:

• AE details
• Drug details
• Dates
• Seriousness criteria
• Medical coding (MedDRA, WHO-DD)
• Narrative information

…are correct and match the source document.

Example:
If CIOMS lists the AE onset as 12 Jan 2025, the case must also show this date consistently in narrative, coding, and chronology.

B. Consistency

QA checks that:

• No contradictions exist across the case sections
• Timeline is logical
• Causality aligns with narrative
• Expectedness assessment matches labelling
• Seriousness matches documented criteria

Example:
If the case is marked “non-serious,” the narrative should not describe “patient was admitted”, which implies seriousness.

C. Alignment with SOPs & Regulatory Guidelines

QA ensures compliance with:

• ICH E2B guidelines
• EU/US reporting rules
• Company SOPs for case processing
• Data privacy policies
• MedDRA/WHO-DD coding guidelines
• Good Pharmacovigilance Practices (GVP Module VI)

D. Formatting Correctness

QA checks formatting such as:

• Proper template use
• Date formats (e.g., DD-MMM-YYYY)
• Structured narrative
• Correct section completion
• Use of accepted medical abbreviations
• Completion of mandatory fields

Proper formatting ensures the case is readable and acceptable to health authorities (EMA, MHRA, FDA).

3. Key QA Checklist Items

A typical QA review includes:

Ø  Minimum 4 criteria present

• Patient
• Reporter
• Suspect drug
• AE

Ø  Seriousness criteria justified and accurate

Ø  Expectedness correctly evaluated

Ø  Timeline correct and logical

Ø  Proper medical coding

Ø  Narrative completeness & clarity

Ø  Causality justified

Ø  No missing mandatory fields

Ø  Follow-up required or not indicated clearly

Ø  Final sign-off recorded

4. Audit Trail Requirements

A complete audit trail must be maintained for:

Ø  Case receipt

Ø  Data entry

Ø  Medical coding changes

Ø  Narrative edits

Ø  Seriousness updates

Ø  Causality revisions

Ø  QA corrections

Ø  Final submission

The audit trail ensures traceability, allowing regulators or auditors to see who made which change and when.

5. Outcome of QA Review

After QA check:

• Case is approved for submission

OR

• Case is sent back for correction (queries raised)

Only after QA approval can the case move to:

• Regulatory submission
• E2B XML generation
• Transmission to EMA/FDA/NCA

6. Example QA Findings (Common Issues Identified)

❌ Incorrect MedDRA PT selected

→ Corrected by QA reviewer

❌ Narrative missing vital medical history

→ Case returned for medical reviewer follow-up

❌ Inconsistent dates between source and database

→ Corrected before submission

❌ Seriousness marked incorrectly

→ Updated based on ICH criteria

❌ Expectedness mismatch with SmPC

→ Corrected during QA

7. Importance of QA Review

Quality Review ensures:

Ø  Regulatory compliance

Ø  Zero data errors

Ø  High-quality ICSRs

Ø  Reduced EMA/FDA rejection rate

Ø  Consistency across global case processing teams

Ø  Strengthening company’s safety governance

It protects both patients and the company.

MODULE 11: REGULATORY SUBMISSIONS

Regulatory submissions in Pharmacovigilance ensure that safety information is shared with Health Authorities (HAs), partners, and global agencies within defined timelines. These submissions can be expedited (rapid/urgent) or periodic (aggregate/summary-based).

1. TYPES OF PV REGULATORY SUBMISSIONS

PV submissions are broadly categorized into:

✅ A. Expedited Submissions (Individual Case Safety Reports – ICSRs)

These involve serious and unexpected adverse events (SUSARs) that must be reported quickly.

✅ B. Periodic/ Aggregate Submissions

Summary safety reports submitted at defined frequencies (6-monthly, yearly, etc.).

A. EXPEDITED SAFETY SUBMISSIONS

Expedited submissions are applicable when a case fulfils:

✔️ Seriousness (ICH criteria)

AND

✔️ Unexpectedness

AND

✔️ Causally related to the drug

Such cases qualify as:

• SUSARs (Suspected Unexpected Serious Adverse Reactions) in clinical trials
• Serious ICSRs in post-marketing

1. Format for Expedited Reporting

➡️ E2B R3 XML Format

This is the international standard for transmitting ICSRs electronically.

It includes structured fields for:

• Patient information
• Drug data
• AE details
• Causality
• Medical history
• Reporter information

The XML file is validated and sent via electronic gateways (FDA ESG, EMA EudraVigilance gateway).

2. Where Are Expedited Reports Submitted?

Global Health Authorities

• FDA (USA) → FAERS
• EMA (Europe) → EudraVigilance
• MHRA (UK) → MHRA Gateway
• CDSCO (India) → PvPI

Business Partners / Affiliates

• License partners
• Co-marketing partners
• Marketing Authorization Holders (MAHs)
• Global Safety Offices

Submission timelines are partner-specific (usually 24–72 hours).

3. Timelines for Expedited Submissions

Failure to comply may lead to:

• Regulatory actions
• Audits and findings
• Compliance failures

B. PERIODIC SAFETY REPORTS (Aggregate Submissions)

Periodic reports summarize all safety data collected over a defined period, including:

• Reported ICSRs
• Literature data
• Exposure data
• Benefit–risk analysis
• Signal evaluations

Below are the main periodic reports:

1. PSUR (Periodic Safety Update Report)

• Required for marketed products
• Focuses on safety data, worldwide exposure, and benefit–risk
• Submitted to EMA, MHRA, CDSCO, and other authorities
• Frequency: Every 6 months, 1 year, or 3 years

2. PBRER (Periodic Benefit-Risk Evaluation Report)

• Updated version of PSUR based on ICH E2C(R2)
• Includes:
• Safety summary
• Cumulative data
• Benefit-risk evaluation
• Identified & potential risks
• Risk minimization measures

More comprehensive than PSUR.

3. PADER (Periodic Adverse Drug Experience Report) – US FDA

Required specifically by FDA for marketed products.

Includes:

• Summary of AEs
• Line listings of serious unexpected AEs
• Narrative summaries
• Changes in safety profile

Frequency:

• Quarterly for first 3 years
• Annually thereafter

4. DSUR (Development Safety Update Report)

Required for clinical trial safety monitoring.

Summarizes:

• All clinical trial AE reports
• SUSARs
• Summary tabulations
• Cumulative safety data
• Development plan updates

Submitted annually during the trial duration.

Significance of Regulatory Submissions

Ø  Ensures safety data transparency

Ø  Prevents harm by early detection of serious risks

Ø  Informs updates in labeling (SmPC, PI)

Ø  Supports global pharmacovigilance compliance

Ø  Protects company from regulatory penalties

Ø  Maintains product on the market safely

Flow of Regulatory Submission Workflow

1. Case processed & medically reviewed
2. Quality check (QA)
3. E2B XML generation
4. Gateway validation (FDA/EMA)
5. Error correction (if needed)
6. Final submission
7. Submission confirmation stored in database

MODULE 12: RISK MANAGEMENT

Risk Management in Pharmacovigilance involves identifying, characterizing, preventing, or minimizing risks associated with a medicinal product throughout its lifecycle. It ensures that the benefit–risk balance of a product remains positive for patients.

Risk Management is required by global regulators such as EMA, FDA, and CDSCO.

1. WHAT IS RISK MANAGEMENT?

Risk management is a continuous, proactive, and systematic process that includes:

·         Identifying risks

·         Assessing risks

·         Monitoring risks

·         Minimizing risks

·         Communicating risks (to HCPs, patients, regulators)

Risk management is documented and guided through a formal Risk Management Plan (RMP).

RISK MANAGEMENT PLAN (RMP) COMPONENTS

An RMP is a detailed safety document required for:

• New drug approvals
• High-risk products
• Products with identified safety gaps
• Biologics
• Advanced therapies

It includes three core sections:

1. SAFETY CONCERNS

Safety concerns describe the specific risks associated with the medicinal product.

Safety concerns are divided into:

A. Important Identified Risks

Risks that are confirmed and supported by evidence.

Examples:

• Hepatotoxicity confirmed in clinical trials
• Anaphylaxis reported post-marketing

These require active monitoring and sometimes additional risk minimization.

B. Important Potential Risks

Risks suspected but not yet confirmed; evidence is incomplete.

Examples:

• Possible risk of QT prolongation
• Potential risk of renal toxicity seen in preclinical studies

These require special monitoring, often through targeted pharmacovigilance activities.

C. Missing Information

Areas where safety data is insufficient.

Common categories:

• Use in pregnancy
• Use in breastfeeding mothers
• Long-term safety
• Safety in children or elderly
• Limited data in renally/hepatically impaired patients

These gaps require additional studies or monitoring plans.

2. PHARMACOVIGILANCE PLAN

This section describes actions needed to investigate, monitor, or further evaluate safety concerns.

The PV Plan includes:

A. Additional Pharmacovigilance Activities

These are studies or actions conducted beyond routine PV.

Examples:

• Post-authorization safety studies (PASS)
• Intensive monitoring programs
• Registries
• Observational studies
• Active surveillance systems

These helps confirm or rule out important potential risks.

B. Targeted Follow-up Questionnaires

Follow-up forms designed to capture detailed, standardized information for specific AEs.

Examples:

• Hepatotoxicity questionnaire
• Anaphylaxis follow-up form
• Pregnancy exposure and outcome form
• Cardiac arrhythmia follow-up form

They help ensure complete and consistent clinical data is obtained.

3. RISK MINIMISATION MEASURES (RMMs)

RMMs help prevent or reduce the occurrence or severity of adverse reactions.

Divided into:

A. Routine Risk Minimization Measures

Integrated into normal drug use.

Include:

• Product labeling (SmPC → Summary of Product Characteristics)
• Patient Information Leaflet (PIL)
• Contraindications
• Warnings & precautions
• Dose adjustments
• Drug interactions listed
• Monitoring recommendations

Routine measures are mandatory and form the base risk control system.

B. Additional Risk Minimization Measures (aRMMs)

Required when routine measures are not sufficient.

These include:

1. Educational Materials

For HCPs or patients
Examples:

• Guide for prescribers
• Patient alert cards
• Risk awareness brochures

2. Controlled Access / Restricted Distribution Programs

Used for high-risk medications.

Examples:

• Pregnancy prevention programs (e.g., isotretinoin)
• REMS programs (Risk Evaluation and Mitigation Strategies – FDA)

3. Training Programs

Mandatory HCP training before prescribing.

4. Communication Plans

Direct communication to healthcare professionals (DHPC letters).

Additional RMMs are monitored for effectiveness regularly.

IMPORTANCE OF RISK MANAGEMENT

Risk management:

• Prevents harm to patients
• Ensures early identification of safety issues
• Guides regulatory decisions
• Supports safe use of medicines
• Strengthens benefit-risk profile
• Protects company from regulatory penalties

It is a cornerstone of modern PV systems.

RMP LIFECYCLE

1. Identify risks
2. Update RMP with new information
3. Implement PV plan
4. Apply risk minimization measures
5. Monitor effectiveness
6. Revise and resubmit RMP as needed

RMPs are living documents and updated periodically.

MODULE 13: SIGNAL DETECTION

A signal is: “Information that suggests a new causal association or a new aspect of a known association between a medicinal product and an adverse event.”

A signal does not confirm causality—it indicates that further evaluation is required.

Sources of Signals: Signals may come from:

A. Spontaneous Reporting Systems

• Individual Case Safety Reports (ICSRs)
• Company safety database

B. Scientific Literature

• Case reports
• Drug safety studies

C. Clinical & Epidemiological Studies

• Clinical trial data
• Post-marketing studies

D. Periodic Reports

• PSUR / PBRER
• DSUR
• PADER

E. Other Sources

• Social media (some agencies consider)
• Patient support programs
• Drug utilization data

Steps in Signal Detection

Step 1: Data Collection

Sources include:

• Safety databases (global & local)
• Literature screenings
• Periodic reports (PSUR, PBRER)
• Regulatory agency reports (e.g., FDA FAERS)
• Clinical trial data (DSUR)

Objective: Gather all AE data and identify unusual patterns.

Step 2: Statistical Methods

Used to detect disproportionality—i.e., whether a drug-event pair is reported more often than expected.

Common tools:

• PRR (Proportional Reporting Ratio)
• ROR (Reporting Odds Ratio)
• IC (Information Component – Bayesian)

Example:
If “Drug X – Liver Injury” shows a PRR > 2 → potential signal.

Step 3: Medical Review

Medical experts evaluate:

• Clinical relevance
• Biological plausibility
• Severity & medical seriousness
• Case quality (dechallenge/rechallenge)
• Time-to-onset pattern
• Consistency across cases

Outcome: Decide if the signal seems medically meaningful.

Step 4: Signal Validation

Determine whether the signal is:

• Valid
• Not valid
• Needs more data

Criteria used:

• Case quality
• Plausibility
• Consistency across sources
• Exposure data

Step 5: Signal Prioritization

High priority signals:

• Serious AEs (death, life-threatening)
• High frequency
• Preventable issues
• High public health impact

Low priority signals:

• Non-serious & rare events
• Weak biological plausibility

Step 6: Signal Assessment

A deep evaluation involving:

• Causality assessment
• Benefit–risk impact
• Case series analysis
• Literature review
• Comparison with similar drugs

Step 7: Regulatory Actions (If Confirmed)

Actions may include:

• Safety label update
• SPC / PI revisions
• Boxed warning addition
• Risk Minimisation Measures (RMMs)
• Updating RMP
• Health authority communication (DHPC, alert)

Examples of Signals

6. Important Terms

New Signal

Previously unknown; requires investigation.

Emerging Safety Issue

Urgent signal requiring immediate communication.

Potential Signal

Needs more data; not yet validated.

7. Case Example of Signal Detection

Drug: "Cardiotab"
Reported AE: Arrhythmia
Data:

• 15 cases reported in 3 months
• PRR = 3.5 (significant)
• Consistent time-to-onset (1–3 days)
• 3 positive rechallenge cases
• Plausible mechanism (QT prolongation)

Outcome:
→ Validated signal
→ Label updated
→ ECG monitoring added as RMM

MODULE 14: BENEFIT–RISK EVALUATION

Benefit–Risk Evaluation is a continuous, systematic assessment of how the therapeutic benefits of a drug compare against its known and potential risks, using new evidence throughout the product lifecycle.

It ensures that the benefit–risk balance remains favourable for patients.

Key Components of Benefit–Risk Evaluation

1. Case Trends

PV teams monitor:

• Increase in frequency of specific adverse events
• New patterns (e.g., clustering in certain age groups)
• Changes after market expansion
• Trends linked to comorbidities or drug interactions

Why important?
Rising AE trends may signal:

• A new risk
• Worsening of an existing risk
• Need for regulatory action

2. New Safety Findings

From:

• Literature
• ICSRs
• PSUR/PBRER
• Clinical trials
• Epidemiological studies
• Regulatory alerts (FDA/EMA safety communications)

New findings may include:

• New serious adverse reactions
• Increased severity/frequency of known events
• Drug–drug interaction risks
• Off-label risks

3. Efficacy Updates

Benefit side includes:

• New clinical evidence of efficacy
• Real-world performance data
• Subgroup effectiveness (e.g., elderly, children)
• Comparison with competitors or standard therapy

If benefits decrease → risk–benefit may turn unfavourable.

4. Risk Minimization Outcomes

Evaluate how well implemented RMMs are working:

• Are risks decreasing after label updates?
• Are prescribers using the medication safely?
• Are educational materials effective?
• Are high-risk populations avoiding the drug?

Examples of routine RMMs:

• Label updates
• SmPC/PIL warnings
• Boxed warnings

Examples of additional RMMs:

• Controlled access programs
• Prescriber training
• Patient guides

5. Regulatory Decisions

Regulatory bodies continuously assess:

• Whether benefit > risk remains appropriate
• Need for updated warnings
• Need for restriction of indications
• Requirement for post-authorization safety studies (PASS)
• Whether product should remain on the market

Possible decisions:

• Label changes
• RMP updates
• Safety alerts (e.g., DHPC)
• Product recall or suspension

Example (PV Case-Based)

Drug: CardioSafe
Benefit: Reduces stroke risk by 40%
New Finding: 20 new cases of severe liver injury
Trend: Increasing in elderly patients
RMM Outcome: No change despite warnings
Efficacy Update: Benefit remains high but less effective in renal impairment

Benefit–Risk Conclusion:
→ Additional RMMs needed
→ Update labeling to warn elderly
→ Require liver function monitoring

MODULE 14: SPECIAL SCENARIOS HANDLED BY A PSA

Patient Safety Associates (PSAs) must manage certain high-priority, complex, or sensitive case types, as these situations have greater regulatory importance and require specialized documentation and follow-up.

Below are the key special scenarios, their definitions, required actions, and examples.

1. Pregnancy & Lactation Exposure

Why special?

• Risk to fetus/infant
• Limited data available
• Regulatory requirement for close monitoring

When reported?

• Drug exposure before conception, during pregnancy, or during breastfeeding

PSA Responsibilities

• Capture trimester, maternal health, dose, duration
• Collect pregnancy outcome (live birth, miscarriage, stillbirth)
• Follow-up until outcome is known
• Complete pregnancy follow-up form

Examples

1. Woman takes isotretinoin during early pregnancy → potential teratogenic risk
2. A breastfeeding mother reports infant diarrhea after maternal antibiotic use

2. Paediatric & Geriatric Safety

Paediatrics

• Children have different PK/PD responses
• Higher vulnerability to dosing errors
• Off-label use is common

PSA Actions:

• Capture age in days/years
• Check for weight-based dosing
• Confirm off-label use

Geriatrics

• Polypharmacy
• Organ impairment → greater ADR risk

PSA Actions:

• Capture comorbidities
• Collect concomitant medications

Examples

• Child receives adult dose → excessive sedation
• Elderly patient develops severe bradycardia due to drug interactions

3. Overdose

Definition

Administration of a larger-than-recommended dose, intentional or accidental.

PSA Actions

• Identify dose taken vs. recommended dose
• Capture symptoms, treatment, and outcomes
• Determine if overdose was intentional (suicidal) or unintentional (accidental)

Examples

• Patient accidentally takes double dose of warfarin
• Intentional overdose of antidepressant reported as suicide attempt

4. Medication Errors

Types

• Prescribing error
• Dispensing error
• Administration error
• Monitoring error

PSA Responsibilities

• Identify stage of error
• Capture root cause (look-alike/sound-alike, wrong route, miscalculation)
• Determine whether AE occurred or not (both reportable)

Examples

• Wrong drug dispensed due to look-alike packaging
• Nurse administers IV drug intramuscularly

5. Off-Label Use

Definition

Use of a drug outside approved indication, dose, route, age group.

PSA Responsibilities

• Document indication and reason
• Assess seriousness and outcome
• Identify if off-label contributed to AE

Examples

• Antipsychotic used in children outside approved age
• Higher-than-approved dose leading to hypotension

6. Device-Related Events

Applies to:

• Drug-delivery devices (pens, inhalers, syringes)
• Combination products
• Medical devices included with drug kits

PSA Responsibilities

• Record device type, batch, lot number
• Capture malfunction details
• Determine user error vs. device failure

Examples

• Insulin pen malfunctions and delivers no dose
• Inhaler blocker causes improper drug delivery

7. Lack of Efficacy (LOE)

Definition

Drug does not produce the expected therapeutic effect.

Why special?

For some drugs (e.g., antibiotics, vaccines, antiepileptics), LOE can be life-threatening.

PSA Actions

• Verify indication, compliance, correct use
• Capture clinical condition before and after treatment
• Identify drug resistance (if applicable)

Examples

• Antibiotic fails to control infection → hospitalization
• Asthma inhaler ineffective due to poor technique

Summary Table