CR-023

Drug Lifecycle Safety Management

and Pharmacovigilance Compliance

Module 5
Overview of Module 5

Regulatory requirements (Canada, US, EU)

Safety Summary reports

GVP inspections and audits

Overview of Module 5

Regulatory requirements (Canada, US, EU)

Safety Summary reports

GVP inspections and audits

High Level overview of global regulatory
landscape

Note: CR-015 is a dedicated course on PV regulatory guidelines

Current Safety Environment
Increasing demands for safety data:
• All Serious Adverse Events (SAEs)
• Follow all AEs/SAEs till resolved or stable
• Additional adverse events of interest (e.g. cancers, MIs, hepatic events)
• Bill C-17 - Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law
2014) in Canada
• Pregnancy outcomes
• Food and Drug Administration Amendments Act of 2007 (FDAAA): Provides
FDA with additional requirements, authorities, and resources with regard to
both pre- and post-market drug safety
• Global reporting to EMA and regulatory agencies of EU member states
– Use of CIOMS form
– Country of origin of AE
ICH Definition and Background
International Conference on Harmonisation of
Technical Requirements for the Registration of
Pharmaceuticals for Human Use

▪ Joint international regulatory/industry project

▪ To improve (through harmonization), efficiency of
development/registration of new medicinal products
▪ Based on scientific consensus
▪ Commitment by regulatory parties to implement ICH
recommendations

https://www.ncbi.nlm.nih.gov/books/NBK174229
EMA- European Medicines Agency
The European Medicines Agency (EMA) is a EU agency for the evaluation
of medicinal products. Prior to 2004, it was known as the European
Agency for the Evaluation of Medicinal Products (EMEA)

Committees National (non-EU) responsibilities

1. Medicinal Product for 1. Spontaneous reporting systems
Human Use 2. Risk Management system enforcement;
2. Medicinal Product for regulatory decisions
Veterinary Use 3. Reporting Systems
3. Orphan Medicinal Products 4. Competent Authority
4. Herbal Medicinal Products 5. Enforcement Agency / Inspectorate
5. Pediatric 6. Obligation to conduct repeated
6. Advanced therapies inspections of compliance
7. Pharmacovigilance and Risk 7. Requirement to apply dissuasive,
Management proportionate and effective measures in
relation to compliance

http://www.ema.europa.eu/ema/
Pre-marketing Safety reporting EU
 Post-marketing safety reporting EU
1. EudraVigilance
2. Mandatory electronic reporting
3. Only include medically confirmed reports
4. Require QPPV
5. Rapid alert system EU, there are no harmonized rules for post-
marketing studies
6. EMA requires a PSUR every 6 month for 2 years, and annually
for 3 more years
7. Prescription-Event Monitoring system – postmarketing
surveillance technique designed to monitor the overall safety of
newly marketed medicines (UK) for the first 10000 patient using
a new drug
EduraVigilance
The US Regulatory Environnement
FDA’s Role and Responsibilities:
▪ Regulation of drugs, foods, cosmetics, biologics, medical devices
▪ Administration, enforcement, interpretation of US drug law and
establishment of regulations which have the force and effect of
law
▪ Developping policies, procedures and regulations to implement its
reglatory initiatives, some going beyond the intent of the original
laws
▪ Drug Registration in the US = one of the most rigorous systems in
the world
FDA Pharmaceutical product management
Pre-marketing Safety reporting US
 Post-marketing safety reporting US
▪ AERS
▪ MedWatch Program (Voluntary and Mandatory)
▪ Optional electroinc reporting
▪ NDA Annual reports to FDA
▪ Consumer reports; «Dear HCP» letters
▪ Expedited reporting of all class action lawsuits
▪ Clinicians are encouraged to report ADRs to MAHs or FDA (not
mandatory)
▪ NDA periodic reports quarterly during the first 3 years after
approval and annual reports thereafter
MHRA: Medicines and Healthcare products
Regulatory Agency
MHRA is an executive agency of the Department of Health in the UK responsible for ensuring that
medicines and medical devices work and are acceptably safe.
▪ Assessment and authorization of medicinal products for sale and supply in UK.
▪ Operate post-marketing surveillance for reporting, investigating and monitoring of
adverse drug reactions to medicines and incidents with medical devices.
▪ Oversee the Notified Bodies that ensure medical device manufacturers comply with
regulatory requirements before putting devices on the market.
▪ Operate a quality surveillance system to sample and test medicines to address quality
defects and to monitor the safety and quality of unlicensed products.
▪ Investigate internet sales and potential counterfeiting of medicines, and prosecute where
necessary.
▪ Regulate clinical trials
▪ Monitor and ensure
▪ Promote safe use of medicines and devices.
▪ Manage the Clinical Practice Research Datalink and the British Pharmacopoeia.

https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
 Japan
▪ In Japan, the authorities require a survey on a cohort of a few
thousand patients established by a certain number of identified
institutions during the 6 years following authorization.
▪ Systematic information on this cohort, taking into account a
precise denominator, must be reported annually.
▪ Regarding other marketing experience, adverse reactions which
are non-serious, but both mild in severity and unlabeled must
be reported every 6 months for 3 years and annually thereafter.
 Canadian PV Regulatory
environment
Develops and enforces regulations under Government of Canada legislation
▪ consults with the Canadian public, industry and other interested parties in the
development of laws that protect health and safety
▪ prepare guidelines and policies in order to help interpret and clarify the
legislation surrounding drugs and health products.

Activities of the Marketed Health Products Directorate (MHPD) include:

▪ monitoring and collecting adverse reaction and medication incident data;
▪ reviewing and analyzing marketed health product safety data;
▪ conducting risk/benefit assessments of marketed health products;
▪ communicating product related risks to health care professionals and the public;
▪ overseeing the advertising regulatory requirements of health products; and
▪ providing policies to effectively regulate marketed health products.

http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/mhpd-dpsc/index-eng.php
http://www.hc-sc.gc.ca/dhp-mps/index-eng.php
 Health Canada’s Role in Drug Regulation
• safety, efficacy, quality: including pathways to market that allow
accelerated approvals
Pre-market • Risk management planning: link between what risks are known or
anticipated at time of drug approval, and plans to monitor and study

• New indications and/or expansion of patient population to be treated

• New safety information (adverse events, interactions, studies)
Post-market • Changes in market place availability of safer/cheaper therapeutic
alternatives

• Provinces and territories: administration of healthcare system,

regulation of health care professionals, holders of much healthcare
Partners and system data
collaborators • Health technology assessors: funding decisions
• International regulators
Health Canada organizational overview
Safety Database:
https://webprod4.hc-
sc.gc.ca/medeffect-
medeffet/index-
eng.jsp

Report an Incident
Involving a Consumer
Product
http://www.hc-
sc.gc.ca/cps-
spc/advisories-
avis/incident/index-
eng.php
Decision Making Framework MHPD
MedEffectTM Canada Initiative
MedEffectTM Canada Initiative
▪ Adverse Reaction Online Database contains information on suspected adverse reaction reports
related to marketed health products that were submitted to Health Canada by consumers and
health professionals, who submit reports voluntarily, as well as by MAH, who are required to
submit reports
▪ Provide centralized access to new safety information about marketed health products
▪ Simple and efficient access to safety information
▪ Easily report adverse reactions
▪ Increase awareness about the importance of reporting adverse reactions
▪ Identify the needs of target audiences for post-market surveillance activities

https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada.html
Good Pharmacovigilance Practices (GVP)
▪ http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2
012/06/WC500129133.pdf

Health Canada GVP- effective: Aug, 2013

▪ http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0102_gvp-
eng.php
 GUI-0102 highlights
Covers the following drugs for human use This guide does not currently apply to:
which are subject to GVP inspections: ▪ hard surface disinfectants,
▪ pharmaceuticals, ▪ veterinary products,
▪ biologics, including biotechnology products, ▪ natural health products,
vaccines and fractionated blood products, ▪ whole blood and blood components
▪ medical gases, and
▪ radiopharmaceuticals.
Prohibition – C.01.016
No manufacturer shall sell a drug unless the manufacturer complies with
the conditions set out in sections C.01.017 to C.01.019.

Serious Adverse Drug Reaction Reporting – C.01.017

The manufacturer shall submit to the Minister a report of all information
relating to the following serious adverse drug reactions within 15 days
after receiving or becoming aware of the information, whichever occurs
first:
▪ (a) any serious adverse drug reaction that has occurred in Canada with
respect to the drug; and
▪ (b) any serious unexpected adverse drug reaction that has occurred
outside Canada with respect to the drug.
▪ complete pharmacovigilance information is provided to Health Canada.
Annual Summary Report and Case Reports - C.01.018
MAHs are to conduct systematic analyses of safety data on a regular (annual)
basis. The annual summary report can be used to identify safety signals or
changes to what is known about the risks and benefits of the drug.
▪ The manufacturer shall prepare an annual summary report of all
information relating to adverse drug reactions and serious adverse drug
reactions to the drug that it received or became aware of during the
previous 12 months.
▪ The annual summary report shall contain a concise, critical analysis of the
adverse drug reactions and serious adverse drug reactions to the drug.

Issue-related Summary Report - C.01.019

The Minister may, for the purposes of assessing the safety and effectiveness
of the drug, request in writing that the manufacturer submit to the Minister
an issue-related summary report to summarize a specific issue with a drug.
Issue-related Summary Report (IRSR)
The information requested in an IRSR should contain, but is not limited to, the following:
• Medical definition of the AR(s) relating to the subject of the report.
• Description of the search strategy to retrieve the cases (e.g., from databases).
• Detailed summary analysis of the cases. Information should include, but not be limited
to: tabulation of all events; MAH comments on the cases; summary analysis of the
temporal relationship between product administration and the occurrence of the event;
and summary analysis of possible risk factors and confounding variables.
• Canadian and international patient exposure data using both patient-years and total
number of patients exposed, if data are available.
• Core reference safety information, finished product labels, PM, labeling standard or
approved labeling information, which reflects the Canadian market entry requirements.
• A conclusion as to the safety and/or the effectiveness of the product with regards to the
occurrence of these events and if applicable, any planned risk mitigating actions or
change to the RMP, PM.
• Copy of all the CIOMS reports for the adverse reaction of interest reported with the use
of the product since its international birth date, if not already submitted. If the volume of
CIOMS reports is large and this becomes prohibitive, contact the requesting bureau to
discuss options.
Maintenance of Records - C.01.020
Good documentation is an essential part of the quality assurance system and
should therefore be related to all aspects of pharmacovigilance.
▪ The manufacturer shall maintain records of the reports and case reports
referred to in sections C.01.017 to C.01.019.
▪ The manufacturer shall retain the records for 25 years after the day on which
they were created.
C.08.007 (h)
New Drugs – C.08.007 (h) and C.08.008 (c) Where a manufacturer has received a notice of
compliance issued in respect of a
C.08.008 (c) ▪ new drug submission,
▪ No manufacturer shall sell a ▪ an extraordinary use new drug submission,
new drug unless the ▪ an abbreviated new drug submission,
manufacturer has, with ▪ an abbreviated extraordinary use new drug
respect to all the submission
manufacturer’s previous ▪ or a supplement to any of those
sales of that new drug, submissions, the manufacturer shall
establish and maintain records, in a manner
furnished to the Minister. that enables an audit to be made,
respecting...
▪ (h) any unusual failure in efficacy of that
new drug.
Need for modernizing HC systems
▪ Current regulatory system designed for a different time, limited
consideration of healthcare system needs
▪ Health Canada must become more flexible and adaptable by
▪ contributing to the reduction of lag times between new product reviews
and funding decisions
▪ prioritizing the review of therapeutic products that meet healthcare
system needs
▪ increasingly using post-market data to inform regulatory decisions across
the product lifecycle
Leveraging data for assessing drug safety and
effectiveness
Office of Pharmacoepidemiology and Data
Analytics (OPEDA) MHPD
Drug label changes by data source
Managing the risk of drug product use

Medication or Device
Known Side Effects Product Defects
Error

Avoidable Unavoidable
ICH Q9
Efficacy Quality
Preventable
Safety Adverse
Events

Unexpected Injury or
Consequences Death

Public Health

Source: basic model adapted from FDA (1999). Managing the Risks from Medical Product Use.
Overview of Module 5

Regulatory requirements (Canada, US, EU)

Safety Summary reports

GVP inspections and audits

Drug Safety Update Reports
ICH E2F – guidance on harmonized format, content and timing of
periodic safety reports for development products (including
products that are marketed)

Purpose and content

▪ Provides information on the safety profile of an Investigational
Medicinal Product (IMP)
▪ Provides comprehensive annual review and evaluation of pertinent
safety information
▪ Examines if information is in accord with previous knowledge
▪ Describes new safety issues that may impact on clinical trial subjects
▪ Summarises current understanding and management of identified and
potential risks
▪ Provides update on status of development programme and study
results
DSUR submission
▪ Submitted in EU, US, JP, Eastern Europe, some Emerging
Markets
▪ Submitted to Competent Authorities and/or Ethics Committees
in whose territory a clinical trial is being conducted
▪ Actual requirement may depend on study status
▪ Reports are required for as long as clinical trials are ongoing or
IND is open and active
▪ A DSUR should be submitted separately from the PBRER for the
same product, though reporting periods may be aligned
▪ Submitted annually to CAs and/or ECs within 60 days of DLP
PSLL (periodic safety line listing) reports
▪ EU guidance CT-3 and national legislation requirements
▪ Provide information to Ethics committees, investigators and also
submitted to RA.
▪ Distinct from expedited reporting of individual SUSAR cases
▪ For EU and a number of Rest of the World (RoW) markets
▪ Generally run for 6 months periods and usually aligned with the DSUR
reporting period, with Occasional requests to submit at different
frequency e.g. quarterly
Purpose and content
▪ Provide a listing and summary of SUSARs over a defined period
▪ Blinded and unblinded versions of listings
▪ Unblinded for EC and RA
▪ Blinded for investigators
 DSUR vs PSLL
✓ Annual Safety Report ✓ Bi-annual Safety Report
✓ Source = AZ sponsored clinical trials ✓ Source = all sources
✓ Line Listings of SADRs
✓ Line Listings of SUSARs
✓ Summary Tabulations of SAEs
✓ Unblinded data ✓ ’Safety Summary’ or ’No-SUSAR’ notification
✓ Period cut off date based on DIBD is blinded
✓ SMG deliver ANGEL locator and ✓ Two versions of Line Listing;
report to AZ Regulatory Affairs and ✓ Unblinded to HA and EC/IRB
CRO ✓ Blinded to Investigator
✓ DSUR Executive summary for
IEC/IRB contain important ✓ Period based on last date of last reporting
information. Can be used with period which is aligned with DIBD
supplementary line listings if ✓ Automated production via Jasper
required. Not intended to be ✓ Submission to be recorded in Jasper
submitted to Investigators ✓ Submission to EC/IRB and investigator are
✓ Repository = ANGEL
✓ Submission by MC recorded in performed by Operational Enablement
Register by SMG when MC (Poland HUB)
response to SMG with date ✓ Submission to HA is performed by PS
✓ Recording of submission for DSUR Manager
Executive Summary to EC, in Jasper ✓ Repository = Jasper and ANGEL
by MC Safety
✓ Submission day 59
✓ Submission day 60
Tools for the Collection and Analysis of Vigilance
Data
• Mandatory Adverse Reaction (AR) Reporting
– MAHs are required to submit domestic and foreign adverse reactions and
also reports of unusual failure in efficacy for new drugs
• AR Reporting During Clinical Trials
– The sponsor of a Health Canada-authorized clinical trial, is required to
inform Health Canada of any serious, unexpected adverse drug reaction
that has occurred inside or outside Canada
• Annual Summary Reporting
• Issue-related Summary Report
• Risk Management Plans (RMP)
 PADER (Periodic Adverse Drug Experience Report)

▪ Requirement of US Regulation only

▪ Produced where PBRER is not accepted via waiver, or if required under
terms of the waiver
▪ Most MAH will submit waiver request to submit PBRERs instead of
PADERs

Purpose and content

▪ Provides safety data for marketed products

▪ Narrative summary/analysis of information from the reporting period
▪ Listing and analysis of all 15-day reports submitted in the reporting period
▪ FDA form 3500A or Index of E2B ICSRs for spontaneously reported AEs
in the US that weren’t previously submitted as a 15-day report
Types of aggregate reports
Food and Drug Regulations Canada

The MAH must:

• conduct a concise, critical analysis of the adverse reactions and
serious adverse reactions for a health product and prepare a
summary report with respect to the reports received during
the previous twelve months

• determine whether or not there has been a significant change

in the benefit-risk profile of the health product
Periodic Benefit-Risk Evaluation Report (PBRER)
old term: Periodic Safety Update Report (PSUR)
PBRER is a written document that
summarizes the safety events that
have occurred since the last periodic
report was written and is intended to
provide an update of the worldwide
safety experience of a medicinal
product to local and international
health regulatory authorities at
defined intervals post-authorization.

Each MAH is responsible for submitting PBRERs for its own products
 PSUR PBRER
▪ intended to harmonize the ▪ more attention to benefit-risk
periodic reporting requirements evaluation
to regulatory authorities in a ▪ greater emphasis on proactive
common format and documented risk
▪ Summarize worldwide interval management planning
safety experience of a medicinal ▪ increasing recognition that
product at defined times post- meaningful evaluation of
approval. important new risk
▪ focused on relevant new safety information should be
information in the context of undertaken in the context of a
patient exposure, to determine medicinal product's benefits
if changes were needed to the ▪ greater emphasis on the
Reference Safety Information* cumulative knowledge
(RSI) in order to optimize the regarding a medicinal product,
continued safe use of the while retaining a focus on new
product. information
Periodic Safety Update/Benefit-Risk Evaluation Report
(PSUR/PBRER)
▪ The PBRER/PSUR is an important pharmacovigilance (PV) tool at HC as it
is an important source for overall safety related information:
▪ new safety signals
▪ changes in the benefit-risk profile
▪ effective means of risk communication to regulatory authorities
▪ need for or effectiveness of risk management initiatives
▪ An overview of the safety of the product and includes all ADRs reported
in the period since the last PSUR
together with a summary of the registration status of the product worldwide
▪ actions taken for safety reasons
▪ the worldwide usage of the product and an analysis.
▪ Typically required annually, or semi-annually for the first 3 years on
market.
Not all PSURs have to be submitted to HC but they have to be created and ready to be
submitted upon request

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/vigilance/index-eng.php
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/vigilance/qa_qr_psur-rrp_pecr-rppv-eng.php#q1
PBRER
▪ ICH E2C (R2) - guidance on harmonised format, content and
timing of periodic safety reports for marketed drugs (including
approved drugs under further study)
▪ EU GVP Module VII Periodic Safety Update Reports (Rev 1 April
2013)
▪ FDA Draft Guidance for Industry 2013
▪ MHLW (Ministry of Health, Labour and Welfare) notification 2013
▪ National legislation often states requirement for PSUR but will
accept PBRER

Periodic Reporting Version 2.0

PBRERs
▪ Provides comprehensive and critical analysis of new or emerging
information on the risks of a product, and on benefit in approved
indications, to enable appraisal of product’s overall benefit-risk profile

▪ Contains evaluation of new information relevant to the product, in the

context of cumulative information
• Summarises relevant new safety information that could have an impact on the
benefit-risk profile of the medicinal product;
• Summarises any important new efficacy/effectiveness information that has
become available during the reporting interval
• Establishes whether the information is in agreement with previous knowledge of
the product (as described in the Core Data Sheet [CDS])
• Includes proposed actions to optimise the benefit-risk profile

▪ Assures regulators that MAH is adequately monitoring and evaluating

the benefit-risk profile of our products

Periodic Reporting Version 2.0

PBRERs
▪ Submitted in EU, US, JP, and many RoW countries, including
many Emerging Markets
▪ Requirements are changing (increasing!) very frequently
▪ Required from first authorisation and up to withdrawal of
product from market
▪ Frequency of submission varies according to national or regional
regulatory requirements.
▪ ICH guidance supports global harmonisation of reporting
periods, with allowance for different frequency of reporting. But
not all countries will accept this
▪ Generally submitted within 70 days or 90 days from DLP, though
some countries have different requirements which can bring
challenges

Periodic Reporting Version 2.0

Health Canada PBRER frequency
▪ The need for the submission of a PBRER and the frequency of report
submission to regulatory authorities are subject to national or regional
regulatory requirements

▪ Depend on such factors as approval dates, the length of time the product has
been on the market, and the extent of knowledge of the benefit-risk profile of
the product.

▪ The PBRER format and content are intended to apply to periodic reports that
cover reporting periods of 6 months or longer.
▪ Once a drug has been marketed for several years, national or regional
regulation may allow the frequency of submission to be extended to longer
time intervals, e.g., greater than one year for products considered to have
an established and acceptable profile or considered to be low risk; however,
more frequent PBRERs may continue to be required in other regions.
PBRER Sections
Title Page
Executive Summary
Table of Contents
1. Introduction
2. Worldwide Marketing Approval Status
3. Actions Taken in the Reporting Interval for Safety Reasons
4. Changes to Reference Safety Information
5. Estimated Exposure and Use Patterns
5.1 Cumulative Subject Exposure in Clinical Trials
5.2 Cumulative and Interval Patient Exposure from Marketing Experience
6. Data in Summary Tabulations
6.1 Reference Information
6.2 Cumulative Summary Tabulations of Serious Adverse Events from Clinical Trials
6.3 Cumulative and Interval Summary Tabulations from Post-Marketing Data
Sources
PBRER Sections
7. Summaries of Significant Findings from Clinical Trials during the Reporting Period
7.1 Completed Clinical Trials
7.2 Ongoing Clinical Trials
7.3 Long-Term Follow-up
7.4 Other Therapeutic Use of Medicinal Product
7.5 New Safety Data Related to Fixed Combination Therapies
8. Findings from Non-Interventional Studies
9. Information from Other Clinical Trials and Sources
10. Non-Clinical Data
11. Literature
12. Other Periodic Reports
13. Lack of Efficacy in Controlled Clinical Trials
14. Late-Breaking Information
15. Overview of Signals: New, Ongoing, or Closed
PBRER Sections
16. Signal and Risk Evaluation
16.1 Summary of Safety Concerns
16.2 Signal Evaluation
16.3 Evaluation of Risks and New Information
16.4 Characterization of Risks
16.5 Effectiveness of Risk Minimisation (if applicable)
17. Benefit Evaluation
17.1 Important Baseline Efficacy/Effectiveness Information
17.2 Newly Identified information on Efficacy/Effectiveness
17.3 Characterization of Benefits
18. Integrated Benefit-Risk Analysis for Approved Indications
18.1 Benefit-Risk Context - Medical Need and Important Alternatives
18.2 Benefit-Risk Analysis Evaluation
19. Conclusions and Actions
20. Appendices
PBRER: USA and Europe
▪ USA: The current situation for periodic safety reports on
marketed drugs is different among the three ICH regions.
▪ The U.S regulations require quarterly reports during the first 3 years, then
annual reports. The FDA has recently published proposed rules1 which take
into account the CIOMS Working Group II proposals

▪ In the EU, Council Directive 93/39/EEC and Council

Regulation 2309/93 require reports with a periodicity of 6
months for two years, annually for the three following years
and then every five years, at time of renewal of registration.
Signal management
The signal management process
can be defined as the set of
The signal management process
activities performed to
shall include all steps from
determine whether, based on
initial signal detection; through
an examination of individual
their validation and
case safety reports (ICSRs),
confirmation; analysis and
aggregated data from active
prioritisation; and signal
surveillance systems or studies,
assessment to recommending
literature information or other
action, as well as the tracking of
data sources, there are new
the steps taken and of any
risks associated with an active
recommendations made [IR Art
substance or a medicinal
21(1)].
product or whether known risks
have changed.
Signal Detection case sources
 Signal Detection flow

Disproportional
reporting ratios
(observed/expected)

Individual case review

Aggregate analysis
Periodic reports

Evidence score
•Degree of disproportionality
Seriousness assessment
•Strength of evidence
•Biologic plausibility Unexpectedness
Public Heath Score Disproportionality Score
•# of annual reported cases Temporal occurrence
•Health consequences Multiple signaling countries
•Level of drug exposure Positive Rechallenge

Yes No
Issue Related Summary Reports
Pursuant to section C.01.019 1 of the Food and Drug Regulations, Health
Canada may, for the purposes of assessing the safety and effectiveness of
a drug, request in writing that the MAH submit an Issue Related Summary
Report which contains a concise, critical analysis of the adverse drug
reactions and serious adverse drug reactions to a drug

• Description of the search strategy to retrieve the cases and summary analysis of the
cases: tabulation of all events with MAH comments; summary analysis of the temporal
relationship summary analysis of possible risk factors and confounding variables.

• Canadian and international patient exposure data

• A conclusion as to the safety and/or the effectiveness of the health product with regards
to the occurrence of these events and if applicable, any planned risk mitigating actions
or change to the Risk Management Plan, Product Monograph, or labeling

• Copy of all the CIOMS reports for the adverse event of interest reported with the use of
the product since its international birth date.
Signal Management and continuous Benefit-
Risk Assessment (CoBRA)
Aggregate Safety Reports: overview
Overview of Module 5

Regulatory requirements (Canada, US, EU)

Safety Summary reports

GVP inspections and audits

 GVP Module

• European Medicines Agency and Heads of Medicines Agencies. Guideline on Good Pharmacovigilance Practices (GVP),
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document%20listing_000345.jsp.
Types of GVP inspections
Routine and “for
System and
cause” Pre-authorisation
product-related
pharmacovigilance inspections
inspections
inspections

Announced and
Post-authorization
unannounced Re-inspections
inspections
inspections

Remote inspections

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172400.pdf
Audit/Inspection Flow
Pharmacovigilance Audits and Inspections
▪ Scope
▪ All PV processes and tasks – including those conducted by
affiliates or delegated to another organizations
▪ The quality system in place for PV activities
▪ Any interactions with other departments
▪ Strategic Risk Planning

▪ Internal
▪ Company compliance or quality assurance departments
▪ Global or local

▪ External
▪ Regulatory agencies
▪ Licensing partners
Pharmacovigilance Audit Objective

▪ The newly-revised pharmacovigilance regulations shift the

emphasis of the audit process to the marketing authorization
holder.

▪ The aim of a pharmacovigilance audit is to use objective

evidence to assess the appropriateness and effectiveness of the
implementation and operation of a pharmacovigilance system.

▪ The audit must be clearly documented and can only rely on

verifiable evidence, such as written records and statements.
 Objectives of pharmacovigilance inspections
▪ determine that the marketing authorization holder has
personnel, systems and facilities in place to meet their
pharmacovigilance obligations

▪ identify, record and address non-compliance which may pose a

risk to public health
▪ use the inspection results as a basis for enforcement action,
where considered necessary
Information on the conduct and outcome of pharmacovigilance
inspections and the follow-up and evaluation of the consequences
may be made publicly available as part of the overall transparency
of pharmacovigilance activities.
https://www.canada.ca/en/health-canada/services/inspecting-monitoring-drug-health-products/drug-health-product-inspections.html

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172400.pdf
Pharmacovigilance Audit Checklist
▪ The quality measures in place for the PV system
▪ Standard operating procedures
▪ Training
▪ Organizational charts
▪ Critical processes within the PV system
▪ Personnel qualification
▪ Database and its maintenance, including validation
▪ Agreement and contracts with vendors, and licensing partners
▪ High-risk areas – especially to monitor the effectiveness of
controls and curative actions.
 Pharmacovigilance Audit Checklist
▪ Changes to the PV system since the previous audit
▪ introduction of a new or upgraded database, or changes to
processes and activities to address changing regulatory
requirements.
▪ The outcome of previous audits.
▪ Some areas or processes may never have been audited and so
may need to be prioritized.
▪ Alternatively, an audit may have highlighted shortcomings or
gaps in procedures and recommended changes in an area or
process.
▪ Changes to the organization that could have an impact on
the area/process, e.g. IT support
 Pharmacovigilance Audit Checklist
▪ Changes in staffing, company structure etc:
▪ key managerial function(s)
▪ number and availability of trained and experienced PV staff.
▪ Causes include high staff turnover, gaps in formal training
processes, increased volume of products etc.
▪ Changes to the structure of the PV system that result from
mergers, major company re-organization etc.
▪ Such changes may, for example, lead to an increase in the number of
products for which the system must cater.

▪ Changes to the organization that could negatively impact on the

area/process, e.g. IT support.
Inspection etiquette
▪ Be prepared, professional and on time
▪ Answer all questions to the best of your knowledge
▪ It is OK to say, “ I don’t know”. Never make up information
▪ Have all documents ready
▪ Don’t invite the Inspector for lunch
▪ Can be perceived as bribery
▪ Offer only information that was requested
▪ Ensure proper personnel is available
▪ Never leave Inspector alone- be ready for requests
▪ Document all documents requested and supplied
▪ If possible address findings immediately, before the exi
meeting (i.e.: missing training)
After the inspection- Exit Notice and CAPA
▪ Exit Notice is the official summary of inspection findings
▪ Findings and observations should be consistent with the exit meeting
content
▪ Findings can be Critical, Major or Minor based on which rating is
given
▪ “C”- Compliant
▪ “NC” Non-Compliant
▪ Provide responses to all findings and address observations
▪ Could be a cross collaborative effort with RA/QA, Global etc
▪ Create CAPA: Corrective Action/Preventative Action Plan with
timelines
▪ Inspector has to accept and approve the CAPA before it can be
implemented.
▪ Acceptance of CAPA closes the Inspection
Consequences of regulatory non-compliance
Demonstrated failure to comply with regulations can lead to
serious consequences up to and including:
▪ Suspension of marketing authorization
▪ Monetary fines and penalties levied against the corporation
and/or its key executives and manager
▪ Fines up to 5 % of the MAH’s Community turnover in the
preceding year
▪ In case of continuous infringement: daily fine not exceeding 2.5
% of daily sales
▪ Imprisonment of key executives and managers of the pharma
company

Example:
http://www.medicalnewstoday.com/articles/251891.php
Enforcement of reporting compliance
▪ With respect to efficacy, effectiveness and added value,
governments and industry have big differences of opinion
▪ Not so with respect to Adverse Drug Reactions and
Pharmacovigilance
▪ Industry has no interest in losing their marketing authorization
▪ Industry has no interest in (product) liability
▪ Industry has interest in improving public image

▪ Even though regulatory requirements with respect to

pharmacovigilance are complex and expensive:
▪ Compliance is natural
▪ Safety issues are discussed openly and transparently
▪ (almost) no serious pharmaceutical company would use Drug Safety
spending as an element of cost-cutting