PV Modules

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

Type of Case	Timeline
Fatal / Life-threatening serious cases	7 calendar days
Other serious, unexpected cases	15 calendar days
Clinical trial SUSAR – life-threatening	7 days
Clinical trial SUSAR – other serious	15 days

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

Case processed & medically reviewed
Quality check (QA)
E2B XML generation
Gateway validation (FDA/EMA)
Error correction (if needed)
Final submission
Submission confirmation stored in database