CR-023

Drug Lifecycle Safety Management

and Pharmacovigilance Compliance

Module 4
Overview of Module 4

Establishing and communicating medicinal

product safety for regulatory approval

Post marketing Adverse Event reporting:

sources, processes and requirements

Expedited reporting requirements

Overview of Module 4

Establishing and communicating medicinal

product safety for regulatory approval

Post marketing Adverse Event reporting:

sources, processes and requirements

Expedited reporting requirements

End to end regulatory approach
New Drug Application (NDA - US)
Demonstrating safety for new drug applications (NDA)
An NDA must provide sufficient information, data, and analyses to permit HA
reviewers to reach several key decisions, including

Whether the drug is safe and

The purpose of preclinical work to develop
effective for its proposed
adequate data to undergird a decision that it
use(s), and whether the
is reasonably safe to proceed with human
benefits of the drug outweigh
trials of the drug.
its risks

Clinical trials are conducted to evaluate the drug for its safety and effectiveness
in treating, preventing, or diagnosing a specific disease or condition. The results
of this testing will comprise the single most important factor in the approval or
disapproval of a new drug

Although the goal of clinical trials is to obtain safety and effectiveness data, the
overriding consideration in these studies is the safety of those in the trials. CDER
monitors the study design and conduct of clinical trials to ensure that people in the
trials are not exposed to unnecessary risks.
What about generics?
New drug approval process Canada
Orphan Drugs

•
Current availability of Orphan Drugs in Canada
Patented Medicine Prices Review Board‘s (PMPRB) Orphan Drug
Launch Monitor, published in 2016:
• Analyzes the international approval of designated orphan drugs
and assesses their availability in Canada
• Focuses on a number of select orphan drugs
– Approved in the US and/or EU over the last decade (2005–2014),
– Drugs that only have orphan indications:
includes Canada and the seven PMPRB international
comparator countries (PMPRB7): France, Germany, Italy, Sweden,
Switzerland, the United Kingdom (UK) and the US
PMPRB: key points on orphan drugs

https://www.slideshare.net/raredisorders/canadas-orphan-drug-regulatory-framework-what-health-canada-is-doing-now-
and-what-is-yet-to-come-lizanne-gillhameisen-health-canada
Future for Orphan Drugs

▪ Improving research, approval, and access

▪ Health Canada ongoing effort

▪ explore and examine most effective ways
to involve patients in the review process

▪ Life cycle approach and increasing

transparency

▪ Continue collaborations internationally

to promote
▪ Convergence, and enhance
collaborations
Shortcomings of CT AE data
 Consequences of insufficient safety data
from clinical trials
▪ Unsafe drug approved for marketing

▪ More than half have serious adverse drug

events detected after approval

▪ 10% have Black Box Warning added

▪ Average number of patients exposed prior to

withdrawal approximately 4 million

▪ Example: Vioxx exposed to 20 million patients

before withdrawal
Solutions – Pre and Post Approval
▪ More drug safety information
- Larger and longer trials
- More relevant study populations
▪ More thorough FDA review of protocol design
▪ Proactive FDA pursuit of safety signals
▪ Conditional approval, if safety problems suspected (NOCc)
 Post-market Safety Monitoring
Regulatory agencies monitor product safety through a
variety of mechanisms including
▪ signal detection of the adverse experience safety
reports in databases
▪ requiring and monitoring risk management plans,
periodic safety update reports and post-
authorization safety studies.

Health Canada and other country specific regulatory

agencies are working with public, academic and private
entities to develop methods for using large electronic
databases to actively monitor product safety.

Important identified risks will have to be evaluated

through observational studies and registries.
Health Canada current review process
Post-market Safety Monitoring
Safety issues not identified in clinical development may be seen and
need to be evaluated, which may result in change of the safety
profile of a medicinal product in the post-marketing environment.

▪ Evaluating spontaneous adverse experience reports and

identifying new safety risks include review of
▪ individual reports
▪ review of a frequency distribution of a list of the adverse
experiences
▪ the development and analysis of a case series
▪ various ways of examining the database for signals of
disproportionality, which may suggest a possible association.
Safety monitoring: signal detection
A 'signal' consists of reported information on a possible causal relationship
between an adverse event and a drug, the relationship being unknown or
incompletely documented previously.
Product monograph
▪ A Product Monograph is a factual, scientific document on
a drug product that, devoid of promotional material, describes
the properties, claims, indications and conditions of use of
the drug and contains any other information that may be
required for optimal, safe and effective use of the drug
▪ http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-
demande/guide-ld/monograph/index-eng.php
▪ https://www.astrazeneca.ca/en/our-medicines.html
Guidance on creating compliant PMs

The product monograph, as a document, will be included by

Health Canada as part of the Notice of Compliance respecting a
New Drug Submission or, when appropriate, a Supplement to a
New Drug Submission, an Abbreviated New Drug or a
Supplement to an Abbreviated New Drug Submission.

The product monograph serves as a standard against which all

promotional material, or advertising distributed or sponsored
by the sponsor about the drug can be compared.
Guidance on creating compliant PMs
Without limiting its generality for use as a standard, the
product monograph serves the following purposes

It contains all the representations to be made in respect of the new

drug as required by paragraph C.08.002(2)(k) and C.08.003(2)(h) of
the Food and Drug Regulations.

It fulfils the requirements for adequate directions for use for new
drugs included in a number of Sections having to do with labelling in
Parts C, D, and G of the Food and Drug Regulations.

It identifies the information that is to be provided on request when a

package insert is not included with a new drug product and a health
professional requests information relevant to clinical use.
Guidance on creating compliant PMs

The PM identifies the information that should be provided to the

patient respecting the use of that product [that is (i.e.) Part III,
Patient Medication Information].

Establishes the limitations/ parameters for all advertising,

representations, and promotional or information material distributed or
otherwise sponsored by the sponsor. Subsection C.08.002(2) of the Food
and Drug Regulations prohibits the advertising of a new drug for any use
of the drug or for any claim that has not been the subject of a cleared
submission.

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/
Overall Objectives of Risk Management
Planning Benefit - Risk Optimization
What Risk Management is Not ????
 Risk Management – A Shift in Emphasis
Risk Management = Risk Assessment + Risk Minimization

“New Model” Modify in the light of new safety data

Pre-marketing ISS Safety Specification Approval Risk Management

Risk Assessment Implementation
Pharmacovigilance
◼ Traditional analyses plus Plan ◼ Enhanced PMS/
◼ Anticipated conditions of Communication
± Risk Minimization
use activities
Plan/ Risk Map
◼ Intrinsic/extrinsic risks ◼ Active influence on safe
(identified and potential) use in the market place
◼ Epidemiology of disease ◼ Assessment of RM
◼ Benefit : risk assessment programme
effectiveness

New data
Optimizing Benefit Risk

High

Unacceptable Risk

Risk

Acceptable Risk

Low

Low Benefit High

Transatlantic Terminology – Risk Management
FDA: Together, risk assessment and risk minimization form what FDA
calls risk management. Specifically, risk management is an iterative
process of (1) assessing a product’s benefit-risk balance, (2) developing
and implementing tools to minimize its risks while preserving its
benefits, (3) evaluating tool effectiveness and reassessing the benefit-
risk balance, and (4) making adjustments, as appropriate, to the risk
minimization tools to further improve the benefit-risk balance.

Europe: A set of pharmacovigilance activities and interventions

designed to identify, characterize, prevent or minimize risks relating to
medicinal products, including the assessment of the effectiveness of
those interventions

…..but then along came REMS

Risk Management Plans in Europe Industry
Experience
▪ Previous advice to produce one RMP per active chemical entity now
superseded by one RMP per “medicinal product” i.e by licence
▪ May receive requests to split existing RMPs into multiple
documents
▪ Level of detail required for PASS protocols may be unrealistic at
submission
▪ EU template very duplicative and unsuited to mature products
▪ Overly long and repetitious document (industry view)
▪ Based on EMEA experience : currently undergoing revision
▪ Public access to RMPs is happening and will be
▪ A key focus of future legislation
▪ Adherence to milestone commitments a focus in PV inspections
REMS in the US: Industry Experience
▪ Practical impact of FDAAA and REMS (i.e: Acutane pregnancy registry)

▪ Initial experience indicates that a very conservative approach is being taken

▪ E.g. an extensive REMS requested for a product on the market for
over 10 years in a new indication based on preclinical toxicology
findings thus far not substantiated in clinical use.

▪ Tools for risk minimization depending on type of risk (Clozaril)

▪ Recent FDA inspections have focussed very strongly on compliance with

RMP commitments

▪ FDA have specific expectations for REMS (risk minimization section)

Risk Management and International
Harmonization

International harmonization is wonderful in theory

……….but everyone is harmonizing differently

Global Risk Management Planning
The Challenge of Reconciling the Differences

Europe
ICH E2E +/- Risk
Minimization Plans

US
Japan
RM Guidelines
ICH E2E +
including
EPPV(?)
RiskMAP/REMs
Risk Management Plan Definition
A document that describes a set of pharmacovigilance activities
and interventions designed to
▪ identify
▪ characterize
▪ prevent or minimize risks
related to drug products, and the assessment of the
effectiveness of those interventions (adopted from the European
Medicines Agency definition of a Risk Management System).

(Note: US: REMS)

Why is an RMP needed?
The decision to approve a drug is based on it having a satisfactory balance of benefits and risks
within the conditions specified in the product labeling.

This decision is based on the information available at the time of approval.

The knowledge related to the safety profile of the drug can change over time through expanded
use in terms of patient characteristics and the number of patients exposed.

In particular, during the early post-marketing period the drug might be used in settings different
from those studied in clinical trials and a much larger population might be exposed in a relatively
short timeframe.
Basic Components of a Risk Management Plan

Risk Management Plan

Safety Specification
Summary of important identified risks, important
potential risks and missing information (ICH E2E)

Pharmacovigilance Plan
b
Based on safety specification; Routine PV practices and
action plan to investigate specific safety concerns (ICH E2E)

Risk Minimization
Activities to be taken to minimize the impact of
specific safety concerns on the benefit-risk balance
Global Plan and US RMP Relationships
Global
Risk Management Plan
Safety Specification

ICH E2E

Pharmacovigilance Plan

ICH E2E

Determine if risk minimization

beyond label is warranted

Global Risk
Minimization Strategy
US Risk Minimization Activities
(RiskMap = Risk Minimization Action Plan)
REMS
(Risk Evaluation & Mitigation Strategies)
Global Plan and EU RMP Relationships
Global
Risk Management Plan
Safety Specification

ICH E2E

Pharmacovigilance Plan

ICH E2E

Determine if risk minimization

beyond label is warranted

Global Risk
Minimization Strategy

EU Risk
Minimization Activities
RMP Regional Variations
Global
Risk Management Plan
Safety Specification
Regional Safety
ICH E2E Specification Req

Pharmacovigilance Plan
Regional PV
ICH E2E Requirements

Determine if risk minimization

beyond label is warranted

Global Risk
Minimization Strategy

Regional Risk
Minimization Activities
Risk Management Plans - Canada
Health Canada has adopted and integrated the use of Risk
Management Plans (RMPs) and the International Conference on
Harmonization (ICH) E2E Guideline into the regulatory review of
drugs in Canada in order to:
▪ Support a life cycle approach to drug vigilance;
▪ Enhance the quality of Health Canada's regulatory assessments;
▪ Support Canadians' timely access to safe, efficacious and high
quality drugs;
▪ Support ongoing evaluation of information that could have an
impact on the benefit-risk profile of health products and;
▪ Align drug vigilance with international best practices.
RM Planning in Industry - Critical Success
Factors
▪ Safety governance – support from the top
▪ Comprehensive change management plan
▪ Defined process and roles/responsibilities
▪ Tools and skills to support the process
▪ Partnership, education and training
▪ Early planning in development
▪ Financial planning
RMP Practical Considerations: Planning

When to start RM Planning – CIOMS VI Principles

▪ Early in development; based on non clinical data & information

on closely related compounds
▪ Establish a procedure & Multi Disciplinary Team; advisory
bodies
▪ Determine background data
▪ Ready accessibility of all safety data
▪ Develop a proactive approach
▪ Establish time frames and milestones
▪ Decision making : focus on safety reviews
RMP Financial Implications
Authorship costs
▪ in house staff or outsourcing
▪ Cost of special expertise
➢“it is essential that appropriate specialized experts should
be consulted at all stages”; “Because of the importance of
risk communication it is recommended that appropriate
experts are consulted”
➢Epidemiological expertise
Cost of implementing proposed measures
▪ Risk minimization activities
▪ Post marketing studies
▪ Educational programmes,
▪ Registries, drug utilization studies, etc.
Cost of delays to marketing approval
▪ If the RMP is considered inadequate
The Role of Epidemiology
Critical for the Safety Specification and PV Plan……bridging
the knowledge gap
▪ Defines demographics & expected characteristics of the
target patient population
▪ co morbidities
▪ anticipated AE profile in usual clinical practice
▪ Design of post marketing safety studies/registries
▪ Identification of existing databases
▪ Design of drug utilization studies
▪ Assess effectiveness of risk minimization measures
Key RMP activities described
Routine Pharmacovigilance Activities
▪ For products for which no special concerns have arisen,
routine pharmacovigilance activities are sufficient for post-
approval safety monitoring. This can include monitoring of
the safety profile of the product through signal detection
activities and preparation of reports for regulatory
authorities (i.e., PSURs).

Routine Risk Minimization Activities

▪ Routine risk minimization activities apply to all medicinal
products and relate to standard activities such as product
labelling and limitations on drug pack size.
Key RMP activities described
Additional Risk Minimization Activity
▪ An intervention intended to prevent or reduce the probability
of an undesirable outcome, or reduce its severity should it
occur, which is in addition to the routine risk minimization
activities. Examples include drug administration training or
additional educational material.
Additional Pharmacovigilance Activities
▪ For products for which special concerns have arisen, additional
activities designed to address these safety concerns should be
considered (e.g., safety studies).
http://www.hc-sc.gc.ca/dhp-mps/pubs/medeff/_guide/2015-risk-
risques_management-gestion_plans/index-eng.php
Evaluation of the Need for Risk Minimization
Activities
“ none of the safety concerns was serious and they can be managed by the
means of the proposals in the pharmacovigilance plan. Therefore there is
no need for a risk minimisation plan.”

The sponsor is responsible for monitoring and evaluating the effectiveness of additional risk
minimization activities.

The proposed risk minimization activities should be dependent on an assessment of the risk, the
population, and how the risk changes during the course of the post-market period.

Guidance on the measurement of additional risk minimisation activities can be found in the EU
Guideline on good pharmacovigilance practices (GVP) Module XVI– Risk minimisation measures:
selection of tools and effectiveness indicators.
Potential for Medication Errors
“There were medication errors identified in clinical trials
presumably due to misunderstanding of, or non-compliance with,
drug administration instructions.”

Dose 10 mg 20 mg 40 mg
Shape Round Round Round
Size mm 6.2 x 2.8 7.9 x 3.3 9.8 x 4.3
Colour Pink Light beige Beige
Limitations of human safety database
Table x: Exposure by baseline disease
No of patients
Total (male/female )
Diabetic nephropathy 65 (39/26)
Hypertensive nephropathy 71 ( 47/24)
Glomerulonephritis 207 (143/64)
Other 246 (140/106)

Table y: Special population exposure

Population Number of patients
Children (<12 years) None
Elderly (>75 years) 14
Pregnant or lactating women None
Relevant co-morbidities
57
•Hepatic impairment
243
•Cardiac disease
….
Genetic polymorphism Not applicable
Ethnic origin
•Caucasian 584
•other 5
Importance of ADR as Risk
Important ADR risk:
Not important ADR Risk:
Toxic Epidermal Necrolysis
(TEN)
Flatulence
AE reporting responsibility and outcome
Overview of Module 4

Establishing and communicating medicinal

product safety for regulatory approval

Post marketing Adverse Event reporting:

sources, processes and requirements

Expedited reporting requirements

 Post-market Drug Safety surveillance
• Ethical considerations
– protect & monitor patient safety

• Legal & Regulatory Obligations

– Local marketing companies (MC) are responsible for expedited reporing to
local regulatory authorities in accordance with the local legislation.
– Patient Safety Managers are responsible for being aware of any changes in
the local regulations.
Post Marketing Requirements &
consequences of non-compliance
Requirements
• Expedited case reporting as per
local regulation (e.g.: SADR,
SUSAR)
• Periodic safety reporting (PBRER,
DSUR, PSUR etc. monitoring
safety profile of products)
• Active safety surveillance
• Risk management*
• Labelling
• PASS (EU only)
Consequences of non-compliance
• Patient safety compromised
• Demonstrated failure to comply
with regulations can lead to
litigation
• Suspension of marketing
authorization
• Monetary fines and penalties levied
against the corporation and/or its
key executives and managers
• Imprisonment of key executives and
managers of the pharma company
The importance of post-marketing safety data
Limitations of Clinical Trial Safety Data
principal means of establishing the safety

pre-marketing trials are limited in size

Randomized controlled trials are the

and duration
and efficacy of drugs. However:

exclude high-risk populations (elderly, pediatric,

pregnant, patients with liver/renal insufficiency
etc)
have limited statistical power to detect rare but
potentially serious adverse events in real-world
patients
lack of adequate ascertainment of adverse events and
limited generalizability of trials that exclude high risk
patients
Type A: Predictable, acute, related to mechanism of action
Unlikely to pick up Type B: Idiosyncratic, unpredictable, acute, not related to a known mechanism
Type C: Chronic effects (continuous)
all type of ADRs: Type D: Delayed effects
Type E: End-of-treatment effects
Sources of Post-marketing Safety Data
Post-marketing Pharmacovigilance includes Individual Case Safety Reports
(ICSR) from unsolicited and solicited sources

Unsolicited:
A spontaneous report is an unsolicited communication by a healthcare professional or
consumer to a company, regulatory authority or other organization (e.g. WHO,
Regional Center, Poison Control Center) that describes one or more adverse drug
reactions in a patient who was given one or more medicinal products and that does
not derive from a study or any organized data collection scheme.

Solicited:
Solicited reports are those derived from organized data collection systems, which
include clinical trials, registries, post-approval named patient use programs, other
patient support and disease management programs, surveys of patients or healthcare
providers, or information gathering on efficacy or patient compliance. Adverse event
reports obtained from any of these should not be considered spontaneous.
Definitions are from:
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Step4/E2D_Guideline.pdf
Sources of Post-marketing Safety Data
Post-marketing Pharmacovigilance includes Individual Case Safety Reports (ICSR) from:
Spontaneous (unsolicited) safety reports originate from:
– Health Care Professionals/Consumers
– National Regulatory Authorities or Pharmacovigilance Centres
– Literature*
– Internet: Company controlled websites or digital media sites
– Digital listening activities that gather data from websites or digital media (company
and non-company)

Solicited safety reports originate from Organized Data Collection Programs:

– Early access programs*
– Patient support and disease management programs
– Patient or disease registries
– Market research: patient level diary studies; surveys of patients or healthcare
providers
– Information gathering on efficacy or patient compliance
– Non-interventional studies (real world evidence-RWE)*

* Denotes safety report sources that may be solicited a well as unsolicited. see next slide
Reporting sources: unsolicited vs solicited
Reporting Source Unsolicited* Solicited Either
Health Care Professional/Consumer v
National Regulatory Authorities or Pharmacovigilance Centres v
Company sponsored websites or digital media sites v
Digital Listening v
Literature v
Organized Data Collection Programs:
• Non-interventional studies v
• Early Access (eg named patient supply) programmes v

• Surveys of patients or healthcare providers, for example market research V

• Intensive Post Marketing Surveillance Activities (for example Clinical v

Experience Investigations)
• Patient level diary studies V
• Registries V

• Patient assistance, patient support, and disease management programmes V

• Information gathering on efficacy or patient compliance. V

• Interventional studies v

*Unsolicited reports are treated as spontaneous.

For more details refer to: 8-S13-cv-X Individual Case Report (ICSR) Standards for Case Handling (AZDoc0007119)
Spontaneous safety reports
• Initial contact to the company be the reporter (patient, HCP, consumer or
caretaker etc.) is often via Medical Information (MI) department:

– MI associates collect as much information as possible related to the AE

including consent to follow up
– Provide balanced medical information, (if requested)
• potential side effect
• potential interaction
• use in pregnancy
– Record interaction in database and forward the case to the local PS team

• Company-wide annual AE training ensures that all employees are aware of

Adverse Event reporting requirements and how to recognize an AE.
 Spontaneous Reporting
Continues during the full lifecycle of the product

Early warnings of drug hazards
through switch to OTC (if
appropriate)
Until product
withdrawal/discontinuation
Market approval may be tied to further safety analysis
May provide characterisation of
ADR syndromes including
seriousness, causality,
expectedness
Provision of continuous safety
monitoring
Benefit/risk assessment
Identification of high risk groups
Assists with estimation of
comparative toxicity within
therapeutic classes (typically
during the first 5 years of
marketing)

Influencing factors: Responsible parties to collect:

• Use/sales of drug (increase or decrease)
• Time on the market (decrease over
time)
• ADR profile of similar drugs (increase or
decrease)
• Media influences (increase)
• Pharmaceutical companies: Obligation
to collect, monitor, evaluate and report
• Regulatory Agencies collect and analyse
ADRs
• Independent researchers: Scientific &
medical literature
 Spontaneous Reporting
Advantages
• Surveillance of all forms of adverse events
and other reportable events
• Non-interventional & Real-world usage
• Primary & secondary care
• All healthcare professionals and patients
• Life-cycle safety monitoring
– Day of launch to Over The Counter (OTC)
switch and beyond
• Broad scale coverage
– Entire treated population
– Labelled indications and off-label use
• Inexpensive to run (cost effective)
• Monitor for short & long latency ADRs
• Detects common and rare ADRs
• Available for all medicinal products
– drugs, vaccines, biologicals and medical
devices
Disadvantages
• Delays in reporting
• Generally poor data quality
- Many patients lost to follow-up
• Misleading or missing data
• No control group or active comparator
• Denominator (patient exposure) data
poor
• Difficult to recognise previously
unknown ADRs
• Gross under-reporting of possible ADRs
• Not systematic
• Relies upon a connection being made
between the drug and the adverse event
• Reporting bias towards serious reactions
• Cannot account for poor or non-
compliance
Spontaneous Reporting: Time on market factor
Reporting rates change with time

No. of
ADR Patient
case Exposure
reports

Time (years)
• Exposure to drug increases and continues to grow with time.
• Case reports follow a short time after usage commences with peak reporting
occurring in the first two years or so.
• Thereafter reporting plateaus and then declines quite rapidly. One notable exception
- products used largely by healthcare professionals - for example hepatitis B vaccine.
Literature monitoring for ICSRs

Solicited Reports from scientific literature

• Literature searches include publications involving AZ
products used in interventional/non-interventional studies.
• ADRs identified from articles which specifically describe use
of the AZ product in a study are considered to be solicited.
Unsolicited Reports from scientific literature
• All other ICSRs (not referencing a study source) identified
from publications are considered to be unsolicited.
Early/Special Access Program
Intended for patients with a chronically or seriously debilitating disease or whose
disease is considered to be life-threatening, and who cannot be treated satisfactorily
by an authorized medicinal product or through an ongoing clinical study.

• Treatment option that allows the use of drug prior to regulatory approval and
outside of a clinical trial.
• In exceptional cases an approved product which is not commercially available in the
country, a withdrawn product or a product which is subject to restricted access.
• There are two different types of Early Access programmes:
• Named Patient Supply (NPS)
• Multiple Patient Early Access Programmes (MPEAPs) for a cohort of patients
• Safety Reports (ICSRs) from Early Access may be considered Solicited or Unsolicited,
depending on local country regulations.
• There is considerable variability of terminology between Health Authorities and countries
in reference to Early Access Programmes (EAP), for example:
• EU: Compassionate Use or Named Patient Supply
• US: Expanded Access
• Canada: Special Access Program
Patient Support Program
A PSP is an organized system where a MAH receives and collects information
relating to the use of its medicinal products. Example are post-authorization
patient support and disease management programs, surveys of patients and
health care providers, information gathering on patient treatment compliance
and persistence and/or assist with re-imbursement schemes

Benefits of patient support program

▪ Reducing costs
▪ Increasing adherence
▪ Managing chronic conditions
▪ Driving retention
▪ Promoting wellness•
▪ Maximizing call center resources
 Disease or Patient
Registry

Disease
Oriented
registries
Facilitates
Product
coordination
of care
Registries

Types of An organized program that uses

Registries
Primary observational methods to collect
Health
Care
Physician
Services uniform data on specified
Registries
Registry
Patients by
outcomes in a population defined
clinical by a particular disease, condition
encounters
or exposure.
Market Research
A market research program refers to the systematic collection, recording
and analysis by a marketing authorization holder or their subcontractor of
data and findings about its medicinal products, relevant for marketing
and business development.
 Digital Listening/Monitoring
Digital listening activities may be conducted on social media communities
which may or may not be company controlled.

• Active digital listening is two way, chat areas &

on-line dialogue where comments blogs

are authored and published (in real-

time or delayed responses) by websites online videos
intended audiences in the pharma
company or a third party Digital Listening
supplier/vendor.
Online on-line social
• Passive digital listening is the review message
boards
networks &
communities
of on-line, static posted comments
or ongoing on-line, real-time posted online
forums*
conversation where the pharma
company or the supplier/vendor
*online forums in which people are engaged in discussions, or otherwise share information about
does not engage in dialogue. diseases, treatments and other health or medical practice related matters
Real World Evidence (RWE)
▪ Real world evidence is the clinical evidence regarding the usage
and potential benefits or risks of a medical product derived from
analysis of real world data (RWD).
▪ Real World Evidence is the product of either interventional (e.g.
Large Simple Trials) or Observational Studies which utilise data
collected through observation of “current clinical practice” and / or
patient reported experience.
▪ Non-interventional studies, are included under the definition of
Observational
▪ Studies, and fall under the umbrella of RWE
▪ Can be used to monitor post-market safety and adverse events
Externally Sponsored Research (ESR)
Externally Sponsored Research (ESR) is research that is initiated and managed by
a non-Company Researcher who assumes the legal and/or regulatory
responsibility for the research as defined by applicable regulations and laws of
the country involved.

▪ The research can be Clinical or Non-Clinical in nature. Investigator sponsored

studies have been incorporated in the ESR/ISS/IIT/ILT framework.
▪ ESRs can be:
▪ Investigator Initiated-Sponsored Research (IISR) – unsolicited research
which is planned, designed, initiated and conducted by a non-pharma
Researcher.
▪ Externally Sponsored Collaborative Research (ESCR) - unsolicited or
solicited research which is planned, designed, initiated and conducted
by a non-pharma Researcher.

acronyms change by company

Non-Interventional/Observational Studies
• A non-interventional clinical study is
• a clinical study where the medicinal product is prescribed in the usual
manner in accordance with the terms of Marketing Authorisation
• the assignment of a patient to a particular therapeutic strategy is not
decided in advance by a study protocol but falls within the current
practice
• prescription of the medicine is clearly separated from the decision to
include patients in the study.

No additional diagnostic or monitoring procedures shall be applied to the

patients and epidemiological methods shall be used for the analysis of
collected data
Observational Studies
Several study designs fall within this category of epidemiology
research including:
▪ Cohort studies, including prospective patient registries
▪ Case-control studies, including retrospective chart reviews; and
▪ Database studies using electronic health records (EHR) or 3rd party databases
Non-Interventional Studies (NIS)
Primary data collection studies:
• All AEs should be collected from HCPs
or consumers in the course of the
study unless the protocol defines
otherwise with a due justification for
not collecting certain AEs
• All fatal outcomes should be
considered as AEs and must be
collected
• For studies which are not investigating
a specific AZ product but a general
class of products (for example statins
or proton-pump inhibitors) there is no
requirement to collect AEs.
Solicited Reports
Where AEs are actively collected
from NISs, such ICSRs will be
considered solicited.
Unsolicited Reports
Reports received from primary data
collection studies for AEs which per
protocol are defined as not requiring
active collection, they will be treated
as unsolicited.
Secondary data collection studies:
The collection of AEs is not required.
Post Authorization Safety Studies (PASS)
▪ A PASS (mainly applicable in the EU) is any study relating to an
authorised medicinal product conducted with the aim of:
▪ identifying, characterising or quantifying a safety hazard
▪ confirming the safety profile of the medicinal product
▪ measuring the effectiveness of risk management measures
▪ A PASS may be interventional or non-interventional
▪ A PASS Registry lists all ongoing AZ PASS studies

Typically the EU QPPV should be involved in the review of ANY PASS

Protocol
Post-marketing Surveillance HC- current
state
Planned future state
Pharmacovigilance Process
• Collect and monitor safety data from all sources
Risk (consistent standards)
Detection

• Ongoing analysis and identification of safety signals

Risk (uniform company position)
Evaluation

• Appropriate clarification, communication and action

Risk
Management
Case Processing flow in
Safety Database
Drug Safety Databases
Managed by
Country specific local safety database Pharma
Local Safety
Database Company
▪ In-house
development
Company specific, collecting safety data from all
▪ Off-the shelf
Global Safety local markets, often outsourced
Database solution: Arisg,
Oracle etc
Country specific per local regulatory agency
Regulatory
Agency
regulations
Database

Global repository of cases received from ,

Vigiaccess
participating countries, managed by WHO

http://www.vigiaccess.org/
Global MAH Safety Database
▪ A 21CFR compliant, fully validated safety database is an essential
part of Good Pharmacovigilance Practice.

▪ An accurate and accessible database allows rapid assessment of

data for signal detection, aggregate report production and
statutory electronic reporting of cases to the regulatory
authorities.

▪ Often outsourced to third party vendors who uses a fully

validated system (e.g. ARISg™) which is one of the leading
industry standard pharmacovigilance databases.
Characteristics of a safety database
Complete, validated, user friendly drug safety database system to
process all pharmacovigilance data. In complete compliance with
international regulations, it facilitates management of all the
processes associated with individual case safety reports, including:
▪ All workflow associated with the • Follow up
particular product
• Storage of adverse event
▪ Managing multiple variants of
products, for example, medicines, reporting at any stage of the
vaccines, combination products, product life cycle
medical devices etc.
• Tracking all communication
▪ Reception of new data as it arrives
▪ Data entry • Generating automatic reminders
▪ Data assessment with full multi- & standard letters
lingual support
▪ Automated duplicate case checks • Automated duplicate case checks
Additional key Safety Database characteristics
Security Measures
• Personnel using the drug safety database are assigned roles which ensure
maximum security:
• staff assigned appropriately different levels of access to functions and data to
ensure maximum security for sensitive information.
• Reports are correspondingly generated and distributed allowing only authorized
users to view them or, only where approved, to amend reports.

Compliant Pharmacovigilance Terminology

• The database should be configured to browse and code using multiple versions of
MedDRA® and the World Health Organisation Drug Dictionary as required.
• Ideally it can also be configured to work with third party coding applications.
Additional key Safety Database characteristics
User Friendly Features
• Cases are presented only to trained staff and are represented on case assessment
screens where all key information appears on just one screen. Cases can be
approved and locked.
• The system will accommodate single case reporting sets in a format rapidly
providing all information in an adverse experience report. There is a standardized
set of management reports, with Business Objects to facilitate ad hoc reporting.

Drug Safety Reporting

• The system is designed to facilitate reporting to regulatory bodies from the
moment it is implemented for your company. It will also distribute and track cases
to third parties according to pre-configured criteria. The system supports a variety
of formats including E2B, CIOMS and MedWatch.
AE Database screenshot
Case reporting lead time
Adverse Reaction Data: why patients report
▪ Each report represents the suspicion, opinion or observation of the individual
reporter
▪ Cause and effect relationships have not been established in the vast
majority of reports submitted
▪ Only a small proportion of suspected adverse reactions are reported to
the program, consequently this information must not be used to
estimate the incidence of adverse reactions
How AE reports get to the HC?

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-
submissions/guidance-documents/common-electronic-submissions-gateway/frequently-asked-questions.html
How AE reports get to the FDA?
Overview of Module 4

Establishing and communicating medicinal

product safety for regulatory approval

Post marketing Adverse Event reporting:

sources, processes and requirements

Expedited reporting requirements

What needs to be expedited to the HA?
Expectedness
▪ Pertains to whether an event is expected or unexpected (on
the basis of previous observation, not what might be
anticipated from the pharmacological properties of the
product)

▪ Unexpected: the nature or severity of the adverse event is not

consistent with the applicable product information (e.g.
Investigator’s Brochure for unapproved product, Package
Insert for approved product)
Relatedness (Causality)
▪ No standard international nomenclature
▪ Conveys that a “causal relationship” between the study/drug
product and the adverse event is “at least a reasonable
possibility” [ICH E2A]
▪ Facts (evidence) exist to suggest the relationship
▪ Information on SAEs generally incomplete when first
received
▪ Follow-up information actively pursued
▪ Assessed by:
▪ Reporting health professional
▪ Clinical trial sponsor
▪ Manufacturer
Determination of Causality
Standard determinations include:
▪ Is there [Drug Exposure] and [Temporal
Association]?
▪ Is there [Dechallenge/Rechallenge] or [Dose
Adjustments]?
▪ Any known association per [Investigator’s
Brochure] or [Package Insert]?
▪ Is there [Biological Plausibility]?
▪ Any other possible [Etiology]?
Determination of Causality
Standard determinations include:
▪ NR: evidence for alternate etiology and/or low or no biologic
plausibility
▪ R: reasonable possibility; facts or evidence to substantiate
relationship, and biologic plausibility
▪ Is there evidence to compel change in previous conclusions?

Note:
▪ Use best judgment based on available adequate information
▪ Substantiate with follow-up
▪ Use a conservative approach
 Severe vs Serious
Severity of an AE is a point on an
arbitrary scale of intensity of the
adverse event in question.
▪ Mild: Awareness of signs or symptoms,
but easily tolerated and are of minor
irritant type causing no loss of time
from normal activities. Symptoms do
not require therapy or a medical
evaluation; signs and symptoms are
transient.
▪ Moderate: Events introduce a low level
of inconvenience or concern to the
participant and may interfere with daily
activities, but are usually improved by
simple therapeutic measures; moderate
experiences may cause some
interference with functioning
▪ Severe: Events interrupt the
participant’s normal daily activities and
generally require systemic drug therapy
or other treatment; they are usually
incapacitating
Serious adverse event (SAE) or
reaction is any untoward medical
occurrence that at any dose:
▪ results in death,
▪ is life-threatening, i.e. patient was
at risk of death at the time of the
event; it does not refer to an event
which hypothetically might have
caused death if it were more
severe.
▪ requires inpatient hospitalization or
prolongation of existing
hospitalization,
▪ results in persistent or significant
disability/incapacity, or
▪ is a congenital anomaly/birth
defect.
 Main Points
▪ MAHs and importers should have in place systems and procedures for the
receipt, handling, evaluation and reporting of ADRs that are adequate to
effectively sustain ADR reporting within 15 days of receipt to Health Canada of
domestic serious expected and unexpected ADRs, foreign serious unexpected
ADRs, as well as any follow-up information for initial case reports.

▪ Procedures should be written, regularly reviewed and approved by qualified

personnel (SOPs) and available to all relevant personnel involved in
pharmacovigilance activities before the procedures are effective.

▪ Changes to procedures should be tracked and documented.

▪ Deviations from procedures relating to pharmacovigilance activities should be

documented.

▪ When part or all pharmacovigilance activities are performed by a third party,

MAH and importers should review procedures to ensure that procedures are
adequate and compliant with applicable requirements stated in the Food
VIII. REPORTING FORMATS
A. FDA forms
1- Form 3500A can be requested from FDA offices
– From Internet
– By Fax
– By Mail

2- Copies can be created by:

– Photocopying
– Computer Generation (requires approval from FDA)
– Details are provided in this guideline (margins, fonts, etc…)
The Role of Narratives

▪ Clinical judgment should be exercised by a qualified health

care professional from the MAH to determine what
information should be submitted.

▪ Personal identifiers should only be submitted in accordance

with the collection, use and disclosure provisions of the
Personal Information Protection and Electronic Documents
Act or equivalent provincial privacy legislation.
 Writing the case narrative
Guidance Document for Industry -Reporting Adverse Reactions to
Marketed Health Products
3.3 The Role of Narratives: summarize all relevant clinical and related information:
– patient characteristic
– therapy dates
– medical history
– clinical course of the event(s)
– Diagnosis
– AR(s) including the outcome
– laboratory evidence (including normal ranges)
– other information that supports or refutes an AR (e.g., re-challenge information)
– narrative should serve as a comprehensive, stand-alone “medical story”
– Relevant autopsy or post-mortem findings should be included in the report, and their
availability should be mentioned in the narrative and supplied on request.
• Clinical judgment should be exercised by a qualified health care professional from the MAH to
determine what information should be submitted.
• Information (e.g., ARs, indication, and medical conditions) in the narrative should be accurately
reflected in appropriate data fields of the reporting form.
Form 3500A
 VIII. REPORTING FORMATS
B. VAERS Form for Vaccines

• Appendix D
• Request by phone
• Request by mail
 VIII. REPORTING FORMATS
C. CIOMS I Form for Foreign AEs
▪ CIOMS, working with several member nations and industry, has
developed a format for international AE reporting (CIOMS I form)
▪ Applicants can use an Form 3500A or, if preferred, a CIOMS I form for
submission of 15-day reports of foreign AEs to the FDA.
▪ Applicants cannot use a CIOMS I form for submissions of AEs that occur
within the United States. For these AEs, an Form 3500A must be used.
CIOMS form
 VIII. Reporting Formats
D. Distribution Reports for Biological Products Including
Vaccines
• This section on distribution reports only applies to human biological products
with approved BLAs.
• Distribution reports must include the bulk lot, fill lot, and label lot numbers
for the total number of dosage units of each strength or potency distributed
(e.g., 50,000 per 10-milliliter vials), labelled date of expiration, and date of
distribution of fill lot or label lot. The report must also include information
about any significant amount of a fill lot or label lot that may have been
returned.
 VIII. Reporting Formats
E. Electronic submissions

• The FDA has an online

system for electronic
submission of post
marketing safety reports.

• For drugs:
https://www.accessdata.fda.gov/
scripts/medwatch/

• For Vaccines:
https://vaers.hhs.gov/esub/step1
Expedited Reporting to Reg. Agencies

▪ Notification (submission) designated format to the appropriate

Regulatory Authorities in compliance with the parameters and
timelines specified by legislation and local regulatory guidelines.
▪ An expedited report would be a Report meeting the criteria for
rapid transmission to a Competent Authority (15 or 7 calendar
days)
▪ Completed via electronic gateway (E2B reporting since 2014/15)
to Health Canada
 Written procedures for post-marketing safety
reporting
• SOPs: Each MAH must develop written standard operating
procedures for the surveillance, receipt, evaluation, and
reporting of AEs to the HA.

• The HA will consider the MAH responsible for information

known to its employees, affiliates, and contractors.

• For this purpose, MAH should develop procedures that allow for
expedited handling of AE reports.
• Records of due diligence should be maintained. This applies to
surveillance and processing for both domestic and foreign
reports of AEs.
Local requirements in a Globalized system
What does Health Canada do with the report?
▪ Reports are received and checked ▪ Medical terminology is applied
▪ Report information is entered into a ▪ Check for new safety concerns
database
▪ Share non-confidential details
▪ Seriousness is assessed
https://www.canada.ca/en/health-canada/services/drugs-health-
products/medeffect-canada/adverse-reaction-database.html
Health Canada specific requirements
Summary of Product Characteristics (SmPC)

MAA-mandatory authorization application

https://www.eupati.eu/safety-of-medicines/safety-communication/
Privacy principles in AE reporting