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