Introduction To Pharmacovigilance (PDFDrive)

The Egyptian Pharmacovigilance
Center (EPVC)
Introduction to
Pharmacovigilance
Amr Saad
PhD in Clinical Pharmacy and Pharmacoepidemiology
University of Manchester, UK
Head of the Egyptian Pharmacovigilance Center (EPVC)
Egyptian Drug Authority (EDA)
Risk/Benefit Balance of medications
Medicines are safe! (X)
Approved medicines are safe! (X)
No medicine is safe! (X)
No medicine is without risk! (√)

1
Risk-benefit balance
Unacceptable
Acceptable
2
Emerging safety consideration of
medications
Safety
Quality Efficacy
3
Learning from History
4
Pharmaco - vigilance
• Pharmaco = medicine
• Vigilare = to watch
alert watchfulness
forbearance of sleep; wakefulness
watchfulness in respect of danger; care; caution
the process of paying close and continuous attention
5
WHO definition of pharmacovigilance
• “Pharmacovigilance is the science and activities relating to the

detection, assessment, understanding and prevention of adverse
effects or any other medicine-related problem”
6
Progress in the PV scope
• Adverse reactions
• The science &
activities realting to • Lack of effect
the detection, - Resistance
assessment,
- Interaction
understanding &
prevention of - counterfeiting
Adverse Events or • Quality problems
any other drug
related problem • Dependance & abuse
• Poisoning
• Medication errors
7
Pharmacovigilance in its broadest term
• Continuously Monitoring medicines to determine unrecognized

adverse effects or changes in the patterns of their adverse
effects……
* yellow cards, signals from clinical trials
• Continuously Re-assessing the risks and benefits of medicines,

taking action if necessary to improve their safe use……
* adding information to the SPC (Inserts), restricting use of a drug,
withdrawing a drug.
8
Lifecycle of Pharmacovigilance Data
Data Collation
& Review
Benefit/Risk
Communication Evaluation
Drug Safety
Monitoring
Risk Mgt. Signal Detection
9
Drug safety throughout product life
cycle
Preclinical Clinical trial Market authorization Clinical practice
Clinical Drug Safety
Post Marketing Surveillance
Passive Active
Pharmacovigilance Pharmaco-epidemiology
Tools Tools
► Spontaneous reports ►PMS* studies
► Literature searching
*Post marketing surveillance10

Animal studies
• ADME*
• Acute toxicity
• Sub-acute, chronic toxicity
• Carcinogenicity
• Reproductive toxicity
• Mutagenicity
• Teratogenicity
*Absorption, distribution, metabolism, 11

elim
Clinical trials
No. Study
Phase Purpose Design
subjects subjects
Healthy Open trial, not

I 20-80 Safety, PK/PD
volunteers controlled, not blind
Dosing
Controlled, single
II 20-300 Patients requirement
blind
Efficacy
Controlled, double
III 300-3,000 Patients Efficacy
blind
12
Frequency scale of adverse drug
reactions (ADRs)
Occurrence Frequency
Very common ≥10/100
Common (Frequent) 1/100 -10/100
Uncommon (Infrequent) 1/1000-1/100
Rare 1/10,000-1/1000
Very rare <1/10,000
13
Lag time for adverse drug reactions
(ADRs)
14
Limitations of clinical trials
• Small number of patients studied

• Restricted populations (age, sex, ethnicity)
• Narrow indications
• Short duration of drug exposure
15
The need for pharmacovigilance
 Pharmacovigilance is needed in every country because of

differences in:
■ Drug production
■ Distribution and use ( e.g. indications, dose, availability)
■ Genetics, diet, traditions of the people (e.g. use of herbal remedies, etc.)
■ Pharmaceutical quality and composition (active/inactive ingredients )
 Pharmacovigilance is needed for all drugs including generics

 No drug is 100% safe for all people in all circumstances
 Risks in medicine cannot be reduced to zero
 Differences in sources of APIs, excipients, manufacturing lines & Supply chain
16
ADR classification
• Type A reactions
 Dose-related
 Predictable from drug pharmacology
 Common
 Normally reversible
 May be manageable with dose adjustment
 Example: bleeding with warfarin
• Type B reactions
 Not dose-related
 Unpredictable
 Uncommon
 May be serious/irreversible
 Indicative that drug needs to be stopped
 Example: anaphylaxis with penicillin
17
ADR classification
• Type C reactions – Chronic
 Repeated drug use
• Type D reactions – Delayed
Take time to develop
Carinogenesis, teratogenesis
• Type E reactions - End of treatment
Withdrawal, rebound phenomena etc.
• Type F – Failure
Treatment did not work – therapeutic failure
Vaccines, OCPs
18
Encouraging the practice of
Pharmacovigilance
 Forgotten part of the

daily practice
►Practice concern
• Ethical concern  Discriminate good
practitioners
• Economic concern  Monitor Safety parallel
wise to efficacy
19
Ethical concerns
►Humanitarian concerns: Hippocratic oath “First Do No

Harm”
• To know of something that is harmful to another
person, who does not know, and not telling, is
unethical
• Valid for everyone:
 Patient
 Health professional
 Manufacturer
 Authorities
20
Economical concerns
ADVERSE EFFECTS US study 1994
4th – 6th cause of death

Medication Errors 5% hospital admissions
Occur in 11% patients
Double cost/length of stay
Preventable ARs
Double mortality rate
50% potential preventable
Unpreventable ARs Less than 1% reported
Quality Problems
21
High burden
• Lazarou et al JAMA 1998; 279:1200-1205

 Meta-analysis of 39 prospective studies from US hospitals
 Incidence of hospital admissions due to serious ADRs = 6.7%
 Fatality rate = 0.32% (106 000 individuals)
 4th - 6th leading cause of death
• Pirmohamed M. et al. Br Med J 329:15-19 (2004)
 Incidence of UK hospital admissions due to serious ADRs = 6.5%
 4% of hospital bed capacity
 Fatality rate = 0.15%
 70% avoidable
 Cost to NHS £466 million/year
22
The Egyptian Pharmacovigilance
Center (EPVC)
The Establishment of
Egyptian
Pharmacovigilance
Center (EPVC) and the
Egyptian Guidelines
Amr Saad
Head of the Egyptian Pharmacovigilance Center
Outlines of this part of the presentation
• Cascade of Released regulations and legal framework.

• Being a member with UMC.
• Establishment of the Egyptian Pharmacovigilance Center (EPVC).
• Achievements to date
• What next?
24
PV as a national system
Authority
MAHs HCPs
25
Cascade of Released regulations and legal framework
26
Cascade of Released regulations and legal
framework
1. Ministerial Decree no. 397/1995.
‫ﺇﻧﺸﺎء ﻣﺮﻛﺰ ﻭﻃﻨﻰ ﻟﺮﺻﺪ ﺍﻷﺛﺎﺭ ﺍﻟﺠﺎﻧﺒﻴﺔ ﻭ ﺍﻟﻤﻨﺎﻭﺋﺔ ﻟﻸﺩﻭﻳﺔ‬
National center for monitoring of adverse drug reactions in Egypt
 Article (3)
The Egyptian Pharmacovigilance Center is to be responsible for the
following:
A- Collection and collation of the adverse drug reactions form the
university, educational, governmental, and institutional hospitals, as
well as other healthcare delivery centers all over Egypt.
27
framework
‫ﺗﺸﻜﻴﻞ ﺍﻟﻤﺠﻠﺲ ﺍﻷﻋﻠﻰ ﻟﺮﺻﺪ ﺍﻷﺛﺎﺭ ﺍﻟﺠﺎﻧﺒﻴﺔ ﻭ ﺍﻟﻤﻨﺎﻭﺋﺔ ﻟﻸﺩﻭﻳﺔ‬

Supreme council for monitoring of adverse drug reactions in Egypt
 Headed by the minister of health.
 Members  key members in the pharmaceutical sector in Egypt
28
framework
1995  2010
Trial and error approaches with no tangible steps on the ground
29
framework
‫ﺑﺸﺄﻥ ﺗﺸﻜﻴﻞ ﻟﺠﻨﺔ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ‬
The establishment of the Pharmacovigilance Committee
 Description of the committee.
 Place and periodicity.
 Aims and objectives.
 Members
30
framework
4. Decree of Minister's of Health Assistant no. 2/2010.
‫ﺑﺸﺄﻥ ﺍﻟﻘﻮﺍﻋﺪ ﺍﻟﻤﻨﻈﻤﺔ ﻟﻠﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﻭ ﺃﻣﺎﻥ ﺍﻟﻤﺴﺘﺤﻀﺮﺍﺕ ﺍﻟﺼﻴﺪﻟﻴﺔ‬
Concerning the regulations of Pharmacovigilance and Pharmaceutical
products safety
 WHO accreditation for Regulatory procedures of biological
products.
 PSURs & ICSRs.
31
framework
5. Ministerial Decree number 268/2012.
‫ﺑﺸﺄﻥ ﻣﺮﻛﺰ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﺍﻟﻤﺼﺮﻱ‬
1995 ‫( ﻟﺴﻨﺔ‬398) ‫( ﻭ ﺭﻗﻢ‬397) ‫ﺍﻟﺼﺎﺩﺭ ﻟﺘﻌﺪﻳﻞ ﺍﻟﻘﺮﺍﺭﺕ ﺍﻟﻮﺯﺍﺭﻳﺔ ﺭﻗﻢ‬
Concerning the Egyptian Pharmacovigilance Center (EPVC) and the
modification of previous Ministerial Decrees
 Detailed duties and obligations for MAHs.
 Widening the scope of the Center.
 Satellite centers allover Egypt.
 Upgrading for the center in the hierarchy of the MOH.
32
framework
6. Under Secretary Decree number 47/2012.
‫ﺑﺸﺄﻥ ﺗﺒﻌﻴﺔ ﻣﺄﻣﻮﻧﻴﺔ ﺍﻟﻤﺴﺘﻠﺰﻣﺎﺕ ﺍﻟﻄﺒﻴﺔ ﻟﻤﺮﻛﺰ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﺍﻟﻤﺼﺮﻱ‬
Concerning the establishment of the Medical Device vigilance
department within the Egyptian Pharmacovigilance Center (EPVC)
 establishment of the Medical Device vigilance department.
33
framework
‫ﺑﺸﺄﻥ ﺇﻧﺸﺎء ﻣﺮﻛﺰ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﺍﻟﻤﺼﺮﻯ ﺍﻟﻔﺮﻋﻰ ﺑﺎﻷﺳﻜﻨﺪﺭﻳﻪ‬
Concerning the establishment of the satellite center of the Egyptian
Pharmacovigilance Center (EPVC) in Alex.
 establishment of the the satellite center of the Egyptian
Pharmacovigilance Center (EPVC) in Alex.
34
framework
‫ﺑﺸﺄﻥ ﺇﻧﺸﺎء ﻳﻘﻈﺔ ﺍﻟﻤﺒﻴﺪﺍﺕ ﻭ ﺍﻟﻤﻄﻬﺮﺍﺕ ﻭ ﺗﺒﻌﻴﺘﻬﺎ ﻟﻤﺮﻛﺰ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﺍﻟﻤﺼﺮﻯ‬
Concerning the establishment of the biocides vigilance Department
within the Egyptian Pharmacovigilance Center (EPVC).
 establishment of the biocides vigilance Department within the
Egyptian Pharmacovigilance Center (EPVC).
35
framework
9. New EPVC Guidelines.
‫ﺑﺸﺄﻥ ﺍﻟﻘﻮﺍﻋﺪ ﺍﻹﺭﺷﺎﺩﻳﺔ ﺍﻟﺨﺎﺻﺔ ﺑﻤﺮﻛﺰ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﺍﻟﻤﺼﺮﻱ‬
Guidelines for the Egyptian Pharmacovigilance Center (EPVC)
Marketing Authorization Holders Health Care Professionals

MAHs HCPs
178 pages 29 pages
36
framework
37
framework
38
framework
39
framework
40
framework
10.Registration License.
‫ﺑﺸﺄﻥ ﺍﻟﻘﻮﺍﻋﺪ ﺍﻹﺭﺷﺎﺩﻳﺔ ﺍﻟﺨﺎﺻﺔ ﺑﻤﺮﻛﺰ ﺍﻟﻴﻘﻈﺔ ﺍﻟﺪﻭﺍﺋﻴﺔ ﺍﻟﻤﺼﺮﻱ‬
Guidelines for the Egyptian Pharmacovigilance Center (EPVC)
Tentative Licenses Final licenses

 A very important statement/condition.
 Obligation for MAHs.
41
framework
42
framework
43
Being a member with UMC
44
WHO – International
vigilance system
• Since 2001 (Vigibase)
• Renewed and activated
in 2010 Egyptian
Pharmacovigilance
Center (EPVC)
Human medicines, Medical Cosmetics Veterinary

Biologicals & Biocides
Devices (Future products
dietary supplements (blue cards)
(Pink card) plan) (Future plan)
(yellow cards)
45
WHO drug monitoring programme, 2012
Dark blue: Full members

Medium blue: Associate members
Pale blue: Non members
46
112 Contacts
47
EPVC Position within the Hierarchy of the
MOH
EPVC
Stakeholder for Pharmacovigilance service
in Egypt
Hospitals
Consumers Pharmaceutical
Patients Companies
Community
Preventive Sector
Pharmacies
MOH
Department of
Curative Sector Pharmacovigilance Private Clinics
MOH
Medical
Faculties of
Professions
Medical
UMC Syndicates
Professions
NTI WHO
MedWatch
49
Work Flow
Incomplete Follow Up
Data Data Filtration Data
Generation & Literature Review
Acknowledgment Complete Data Coding Data Entry & Data Analysis
Data
Manufacturers
Hospitals Start Relevant ADR Irrelevant ADR

International
Report Report
Community Point ADR Warning
Pharmacies
Private Clinics Regulatory

Department Further more
Safety Review
Information
Committee
Request
Inspection
Department
Warning Letter
Generation
End ADR Signal No more Info
As Appropriate Detection
Point
Flagged as
ADR Causality
Reporting to Irrelevant
Assessment Report
Uppsala
50
Guidelines & SOPs in place
 Guidelines:
 EPVC guidelines for processing ICSRs
 EPVC guidelines for processing PSURS
 SOPs:
 SOPs for Newsletters
 SOPs for Processing safety issues
 PSUR SOPs
 ICSRs SOPs
51
Achievements to date
52
Time lines during establishment phase
Year 2010 2011
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Month
Drafting plans, timelines,

guidelines & SOPs
Design of workflow, job description
organogram & reporting forms
Secure places, IT, infra-structures
& software
Design the national database &
renew subscription with UMC
database
Design of dynamic bi-lingual
website & on-line submission
Recruitment of personnel
Training of staff
Stakeholder communication &

awareness campaign
Full functioning of the center &
rolling out
53
Achievements to date:
 Drafting plans, timelines, guidelines & SOPs

 Design of workflow, job descriptions, organogram & reporting forms
 Secure places, infra-structures, IT & software
 Establishment of the Pharmacovigilance Committee
 Design the national database & renew subscription with UMC database
 Design of dynamic bi-lingual website & on-line submission
 Recruitment new personnel
 Training of staff
 Stock holder communication & awareness campaign
Red Bullets: initiated not finished

54
Work load during 2010
55
Work load during 2010 to 2012
56
Work load during 2012 compared to
cumulative work load since establishment
57
Work load during
2012 compared to
cumulative work
load since
establishment
58
In/out communications with MAHs
59
Pharmaceutical Restrictions in Use and
Availability – Egypt – Until July 2012 [1]
60
61
62
63
Website:
English face [www.epvc.gov.eg]
64
Website:
Arabic face
65
Database available on the website
66
ADR reporting on the website
67
Training Materials on the website
68
Staff members at EPVC
69
Contact details of EPVC
70
Reporting forms: front page of English
version
71
Reporting forms: back page of English
version
72
Reporting forms: front page of Arabic
version
73
Reporting forms: back page of Arabic
version
74
Reporting forms: Pink card – Front face
75
Reporting forms: Pink card – Back face
76
Reporting forms: Blue card - Antiseptic &
Disinfectant English face
77
Reporting forms: Blue card - Antiseptic &
Disinfectant Arabic face
78
Reporting forms: Blue card - Insecticide
English face
79
Reporting forms: Blue card – Insecticide
Arabic face
80
Implemented levels of regulatory actions in
Egypt based on EPVC decisions
 Asking for specific data from MAH
 Modify the package insert
 Black box warning in the insert
 Boxed warning on the outer pack
 Contraindication
 Newsletter announcement
 Distribute “Dear Dr Letter”
 Preventing importation of specific batches
 Recall of certain batches from the market
 Suspension of the marketing authorization
 Withdrawal of the marketing authorization
81
Published newsletters  40
82
1- WHO acknowledgment (WHO Pharmaceutical
newsletter; 1, 2011; P 15)
83
2- WHO acknowledgment (WHO Pharmaceutical
newsletter; 6, 2012; P 5)
84
What next?
85
What next?
 More awareness for MAHs & HCPs

 Change the culture to encourage reporting
 Strengthen the PV infra structures in the MOH & MAHs
 Consensus in PV activities among MAH
86
Thank you
87
HOW TO REPORT AN ADR ?
Example with DILI
Dr Agnès DEVOIS
France Pharmacovigilance and Clinical Investigation
Division Director
SERVIER
UAE – MOH DUBAI 2013 1

1) On time
2) Relevant information

2
EPIDEMIOLOGY
• DILI is common
• More than 900 drugs, toxins and herbs
• 20% to 40% of fulminant hepatic failure
Drugs : first cause
FULMINANT HEPATITIS
DIVERSITY
> 1000 hepatotoxic drugs
Diverse
mechanisms
VARIETY OF LIVER DISEASES

DEFINITIONS

5
CLASSIFICATION OF LIVER INJURY
• Cholestatic (rare) : increase of over 2 ULN in

ALP alone or R ≤ 2
• Hepatocellular (frequent) : increase of over
2 ULN in ALT alone or R ≥ 5
• Mixed (frequent) : both ALT and ALP are

increased AND 2<R<5
ALT
R=
ALP
Main drugs
responsible for
acute
hepatocellular
hepatitis
Navarro NEJM 2006

RISK FACTORS FOR DILI
• Women
• Alcohol intake
• Age > 50
• NASH
• Viral infection
• Pregnancy

Event reported
Fulminant hepatitis
ALT level
FU +++
Chronic liver diseas
ULN Adaptation
Time
Time
DRUG

PRINCIPLES OF CLINICAL INVESTIGATION
̶ Sources of information are multiple
̶ Target populations may be different across the world
̶ Medical practices may be different from a country to an

other
There is a need of investigating cases in an homogeneous

way, with information relevant enough for evaluators to
provide recommendations regarding any risk.

2
3
Alcohol
Alcohol Drugs
Drugs
Viral
Viral infection 4
Obesity/diabetes
infection
1
NORMAL LIVER TESTS ABNORMAL LIVER TESTS

INCREASE OF LIVER ENZYMES
1
OVERWEIGHT (+/- Metabolic Syndrome)
2
ALCOHOL ABUSE
3 VIRAL INFECTIONS
- Hepatitis A, B, C and E
- Epstein-Barr virus
- Cytomegalovirus
4 TOXIC EXPOSURE
Toxics
- Mushrooms
Drugs
- Paracetamol, NSAIDs, Antibiotics,
Antiepileptics, Statins
5
BILIARY ABNORMALITIES
6 AUTOIMMUNE DISEASES
- Lupus
- Other
7 HEMODYNAMIC TROUBLES
- Heart failure
- Chronic or acute hypovolemia
8 METABOLIC OR GENETIC DISEASES

- Wilson’s disease
- Hemochromatosis
Check the 8 previous points in all

cases.
SERVIER® DRUG-RELATED?
INCREASE OF LIVER ENZYMES
Tool in order to investigate any
“increase of liver enzymes case”

CONCLUSION
• Abnormal liver function tests is not always due to

drugs (4th cause)
• But DILI can lead to death
• Diagnosis of DILI is based on the elimination of
other causes of liver diseases
• A simple algorithm, although artificial, may be
useful to progress into the final diagnosis and to
help in managing the risk

Egyptian Pharmacovigilance Center (EPVC)
Overview of
pharmacovigilance
regulations for Marketing
Authorization Holders
Amr Saad
Head of the Egyptian Pharmacovigilance Center (EPVC)
PV as a national system
Authority
MAHs HCPs
1
Authority
Role of Authority
• Regulations
• Guidelines
• Infra-structures
• Awareness
• Implementation
• Continuous update of regulations to accommodate worldwide
consensus
3
HCPs
What?
•All the suspected ADRs or AEs, including minor ones,

serious & non serious
• Special attention to the
–new medicines,
–new combinations,
–new strength,
–new dosage form
• All serious or unexpected suspected adverse reactions (not in product

information)
• Report if an increased frequency of a given reaction is suspected.
5
What? - Cont.
• Report all suspected ADRs associated with drug-drug, drug food or

drug-food supplements (including herbal and complementary
products) interactions.
• Report ADRs due to medicine abuse
• Report medicine use in pregnancy (teratogenicity) and during
lactation
• Report when suspected ADRs are associated with drug withdrawals.
• Report ADRs occurring from overdose or medication error
• Report unexpected lack of effect (substandard or counterfeiting,
resistance)
6
Progress in the PV scope
• Adverse reactions
• The science &
activities realting to • Lack of effect
the detection, - Resistance
assessment,
- Interaction
understanding &
prevention of - counterfeiting
Adverse Events or • Quality problems
any other drug
related problem • Dependance & abuse
• Poisoning
• Medication errors
7
How ?
The four pillars of a valid ICSR:

An identifiable patient An identifiable reporter
At least 1 of the following: Name, initials
Patient initials Address
Sex Contact details
Weight Qualification (if healthcare professional)
Age at time of reaction or date of birth
Suspected medicine
Suspected adverse reaction
Name (INN and brand name)
Strength (concentration) Description of the reaction
Dose, Frequency Expectedness of the reaction (in accordance
Dosage form with the approved product information)
Route of administration Seriousness of the reaction
Indication for use Date the reaction started, stopped
Duration of use, date started, date stopped Outcomes attributed to adverse reaction
Batch number (especially for vaccines) Relevant tests/laboratory data (if available)
8
How?
Yellow, Pink and Blue cards
Online reporting (www.epvc.gov.eg )

Or
Report to the MAH
9
Who?
• Physicians
• Pharmacists
• Nurses
• Any other Healthcare Professionals
• Pharmaceutical companies (MAHs)
• Patients & their relatives
10
When?
• Simple message :
• Report as soon as drug therapy is suspected to
have resulted in a negative, unintended effect
• Speed is essential
Prioritization of reporting
Is the event
serious?
No Yes
Is the event
unexpected?
No Yes No Yes
Priority 4 Priority 3 Priority 2 Priority 1

To whom?
• Regulatory Authority
• MAH
• Publications & Scientific meetings
MAHs
Pharmaceutical Companies &
Pharmacovigilance
Pharmaceutical Companies are the

main responsible for the safety of
their products (even generics & Biosimilars)
MAH must has an appropriate system of pharmacovigilance in
place
Ensure that all information relevant to the risk-benefit balance of

their medicinal product(s) is reported to the RA fully & promptly
in accordance with legislation (not only ICSRs)
15
framework
16
EPVC Guidelines for MAHs
1. Requirements for Qualified Person for Pharmacovigilance (QPPV)
2. Detailed Description of the Pharmacovigilance System (DDSP)
3. Requirements for Risk Management Systems
4. Requirements for Reporting of Individual Case Safety Reports (ICSRs)
5. Requirements for Periodic Safety Update Reports
6. Company-Sponsored Post-Authorization Safety Studies
7. Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action
8. Guidelines for Marketing Authorization Holders and Competent Authorities
on Pharmacovigilance Communication
17
Routine Pharmacovigilance
Activities
18
1. Detailed Description of Pharmacovigilance
System (DDPS)
• Why
• to prove that the pharmacovigilance system works!
• prove that it has the services of QPPV and
• Prove that it has the necessary means for the collection and notification of adverse
reactions and performing PV activities
• Submission
• Elements
19
DDPS Template
• Cover page
• Table of content
–Hyperlink
• List of Abbreviations
–All abbreviations stated in the DDPS
–Alphabetical order
• DDPS changes history (follow up of versions),
–version number,
–date,
–changes
• DDPS elements/ sections (10 sections)
20
Elements of the DDPS
1. Statement of the MAH and the qualified person regarding their
availability and the means for the notification of adverse reactions
2. Qualified Person Responsible for Pharmacovigilance
3. Organization
4. Documented Procedures in place
5. Databases
6. Contractual Arrangements with Other Persons or Organizations
Involved in the Fulfillment of Pharmacovigilance Obligations
7. Training
8. Documentation
9. Quality Management system
10. Supporting Documentation
21
The change from DDPS to PVMF
DDPS  measure the presence of the system

(10 sections)
PVMF  measures the intelligence of the system

(12 sections = 7 old + 5 new)
22
Components of the PV
System Master File (PSMF)
1) Lists products to which the system described applies, reference to
any other systems [new]
2) Information about Qualified Person for PharmacoVigilance (QPPV)
– job description, qualifications etc, contact details, backup
arrangements and national contacts if present.
3) Organisational structure and sites of PV activities, including third
parties.
4) Location, functionality and responsibility for computer systems.
5) Contracts and agreements for key activities.
6) Description of the key processes, data handling and records of the
pharmacovigilance system [new]
Components of the PV
System Master File (PSMF)
[Cont`d]
7) Description of the quality system.
8) Description of record keeping and archiving.
9) Permanently and readily available, indexed to ensure all
documentation is readily available.
10) Notification of significant changes. [new]
11) Transfer of responsibility for system content and
maintenance. [new]
12) Guidance in Good Vigilance Practise. [new]
2. The Qualified Person for
Pharmacovigilance (QPPV)
• Be appropraitely qualified & experienced/ trianed

• Be a medical doctor or pharmacist or have constant access to medical
expertise
• Be available 24 hours (contact details/phone no.)
• Residing in Egypt
25
Responsibilities
• Maintain / manage PV system
• Oversight of PV system structure, performance (or establish)
• Single contact point for Authorities
• Responsible for ICSRs, PSURs, other reports
• Continuous PV evaluation post-authorization
• Overview of safety and emerging concerns
• Ensures request from Authorities for info on benefit risk is answered fully and
promptly
• Contact point for PV inspections
26
3. Reporting of Individual Case Safety
Reports (ICSRs)
• Minimum information for a valid report

• An identifiable Healthcare Professional reporter;
• An identifiable Patient;
• At least one suspected active substance/medicinal product;
• At least one suspected adverse reaction.
Reports should be followed-up to obtain additional information relevant to the case
as necessary, and relevant follow-up information should be reported to EPVC.
• Reporting:
within15 calendar days (serious ADRs) electronic reporting)+ in the PSUR;
Within 90 days (non serious ADRs, electronic reporting)+ in the PSUR
27
ICSRs Journey
Queries Queries
Reporter/ Data Entry &

QPPV Assessment
Investigator
Regulatory Authorities
4. Requirements for Periodic Safety Update
Reports (PSUR)
• A PSUR is a document prepared & submitted by the MAH to EPVC to provide an
update of the worldwide safety experience of a medicinal product at defined time points
post-authorization.
• PUSR is a MAH specific document (medicinal product all concentration & dosage
forms)
• Contain: ADRs reported worldwide in the period, usage data (patient exposure),
registration status, new regulatory actions, findings from studies…. (Retrospective
data)
• MAHs are expected to provide summary information together with a evaluation of the
risk-benefit balance
• This evaluation should determine whether:
• further investigations need to be carried out and
• whether changes should be made to the marketing authorization and product
information 29
Table of contents for model
PSUR
1. Executive Summary
2. Introduction
Appendices:
3. World-Wide Market Authorization Status
Appendix 1: Company Core Data Sheet/ Company
4. Update of Regulatory Authority or MAH Actions Taken For Safety
Core Safety Information
Reasons
Appendix 2: Summary of product characteristics
5. Changes to Reference Safety Information
Appendix 3: Relevant Post Authorization Safety
6. Patient Exposure Studies (PASS)
• Exposure in clinical trials
Appendix 4: Relevant Risk Management Plan
• Market Experience
(RMP)
7. Presentation of Individual Case Histories
Appended / included Tables:
• “Cases Presented as Line-Listings”
• “Cases Presented as Summary Tabulations”
• “MAH’s Analysis of Individual Case Histories”
Table 1: World-Wide Market Authorization Status
8. Studies
Table 2: Cases Presented In Line Listing
• “Newly Analyzed Studies”
• “Targeted New Safety Studies” Table 3: Cases by Source, Seriousness and
• “Published Studies” Listedness
• “Other Studies”
Table 4: Medically Confirmed Cases by SOC
9. Other information
• “Efficacy-related Information” Table 5: Non-Medically Confirmed Cases by SOC
• “Late-breaking Information” Table 6: Cumulative Summary - Serious and
• “Risk Management Plan” Unlisted Events
• “Risk-Benefit Analysis Report”
10.Overall Safety Evaluation
11.Conclusion 30
Reporting systems in pharmacovigilance
Individual Case Safety Periodic Safety

Report (ICSR) Update Report (PSUR)
Domestic data Domestic & Worldwide data
Spontaneous: Serious  15 days Periodic (PSUR Cycle – IBD  Eu

Non serious 90 days Harmonized date  Eu Reference list)
Egypt Worldwide
MAH ------- CIOMS form MAH ------- PSUR form

HCP------ Yellow Card
One case Collective data
The change from PSUR to PBRER
• PSUR  focus on safety

• PBRER  focus on benefit/risk balance
32
Periodic PSUR submission
• International Birth Date (IBD)…..
Before harmonization
-----------------------------------------------------------------
After harmonization
• EU Harmonized Birth date (PSUR Work sharing and Synchronization

lists),
Dates & Allocated RMS
Effective on July 2012 for a transitional period till
EURD become effective in 4/2013
---------------------------------------------------------------------
• EU Reference Date (URD) (list of European Union Reference
Dates )
Dates & submission frequency
33
5. Overall Safety Evaluation
• During the post-authorization period, New information on the

benefits and risks of the product will be generated,
• On-going evaluation for process the benefits and risks of the
product
• Both the MAH and EPVC must keep up-to-date of all relevant
information in order to fulfill the following responsibilities:
• Ensuring that all sources of information are screened regularly to
identify any potential signals;
• Ensuring that appropriate action is taken in response to new
evidence which impacts on the known risk-benefit balance;
• Keeping EPVC, Healthcare Professionals and Patients informed
34
Overall Safety Evaluation Cont.
Signal Detection and Evaluation

Signals of possible unexpected adverse reactions or changes in severity,
characteristics or frequency of expected adverse reactions may arise from any
source including preclinical and clinical data (e.g. spontaneous reports from
Healthcare Professionals or Consumers; epidemiological studies; clinical trials),
published scientific and lay literature.
Literature screening
• 1x/week, worldwide literature searches for all products (active substance), looking for
ADR reports
• Also, ADRs presented at conferences in abstracts, posters, lectures – Also “local”
publications must be reviewed
• Expedited report for serious ADRs
• Report also in the PSUR if published safety information
35
Overall Safety Evaluation Cont.
It is the responsibility of the QPPV to provide EPVC with any information

relevant to the evaluation of benefits and risks afforded by a medicinal
product, including appropriate information on post-authorization safety
studies.
The MAH should immediately inform EPVC of any prohibition or

restriction imposed by the Competent/regulatory authorities of any
country in the world in which the medicinal product is marketed and of
any other new information which might influence the evaluation of the
benefits and risks of the medicinal product
36
Additional
Pharmacovigilance Activities
37
6. Direct Healthcare Professional Communication
“Dear Doctor-letters” (DDL)
• Defined as information aimed at ensuring safe and effective use of

medicinal products which is delivered directly to individual
Healthcare Professionals by a MAH, or by EPVC.
• should not include any advertising material or statement
• should not be used to provide safety information which does not
require urgent communication
38
• Submission
• the draft DHPC
• a proposed timetable for distribution
• a list of proposed recipients (target groups, e.g. general
practitioners, specialists, coroners, pharmacists, nurses;
hospitals/ambulatory care/other institutions), if appropriate;
• a description of the dissemination mechanism in Egypt where the
DHPC is planned to be disseminated (e.g. by post);
39
7. Company-Sponsored Post-
Authorization Safety Studies (PASS)
A post-authorization safety study is defined as
“pharmacoepidemiological study or a clinical trial carried out in
accordance with the terms of marketing authorization, conducted with
the aim of identifying or quantifying a safety hazard relating to an
authorized medicinal product”.
PASS may be required by Competent Authorities either as a commitment

at the time of authorization or in the post-authorization phase to
further assess a signal. In either case, such studies will be considered
as a relevant part of the Risk Management Plan.
40
PASS Cont.
The MAH who initiates, manages and/or finances the study is responsible for its
conduct and should meet the pharmacovigilance obligations concerning PASS.
The study should be supervised by a designated monitor(s) or monitoring
organization and the names of the monitors should be recorded in the study
documents
The QPPV should be involved in the review of protocols for all post-authorization
safety studies, in order to ensure compliance with pharmacovigilance
requirements.
Pharmacovigilance requirements:
• Evaluation of the Protocol (Ethics committee- new regulation)
• Reporting of Adverse Reactions
• Progress and Final Study Reports (findings & analysis)
41
8. Requirements for Risk  Routine for
Management Plan (RMP) Biologicals
• A risk management system is a set of pharmacovigilance activities and
interventions designed to identify, characterize, prevent or minimize risks
relating to medicinal products (RMP is a prospective document, role of
QPPV)
• Component:
• Part I: Safety specification + PV plan: routine & additional activities to
identify the risks
• Part II: Risk minimization plan: routine & additional activities to
minimize the risk
• Logic
• Identified risk, potential risk ,missing information
• MAH plan
• Submission 42
Egyptian Display of the Eu/Global
RMP
• Not Only for Multinational MAH/Applicant or agent
• Submit
• the most updated version of the Global/EU RMP
• template of “Egyptian Display of the RMP”
• Purpose
• To highlight to what extent the risk management activities (especially
the risk minimization ones) in Egypt adhere to the globally
implemented plan
• To justify any difference whenever exist including the needed tailoring
• Include any additional Egypt/ region-specific risks and the added
activities to manage them
• For follow up with EPVC 43
Subsections
1. Official statement
2. Summary of Risks
3. Summary of Activities and action plans
44
RMP Cont.
Methods for Risk Minimization- Examples
• Provision of Information; SPC , specialized educational program for healthcare professionals and/or
patients
• Legal Status of a Medicine; control who may be permitted to prescribe or dispense a medicine
• Control of Prescription Size or Validity; By limiting the number of units, the patient will need to see
a Healthcare Professional at defined intervals increasing the opportunity for testing and reducing the
length of time a patient is without review (pack size)
• Informed Consent and other Patient Aspects; The Patient signs a form to say that they have been
given the information, they understand it and agree to take part in the trial. This is known as informed
consent. It has potential as a risk management activity to ensure that patients have been provided with
appropriate information regarding the risks of the medicine and appropriate measures to reduce the risks
(e.g Tysabri)
• Patient Registries; Patient registries are often suggested as a means of risk management. They have
been used (sometimes very successfully) in individual countries to record the results of tests, to ensure
that the recommended conditions of use are being adhered to, and control access to a medicine
45
In Summary
46
Safety Evaluation view field
47
PV Responsibilities for MAH
In Place Document to submit

• Has an appropriate system of
Pharmacovigilance ►Detailed Description PV System (DDPS)
with each medicinal product application
• Have a Qualified Person for ►Report serious ARs to EPVC within 15
Pharmacovigilance (QPPV) days (ICSR)
• Implement PV activities ►Submit periodic reports on overall safety
– Collect ADRs of the medicinal product(s) within
– Monitoring for safety signals specified timelines (PSURs)
– Weekly screening of the published literature
• PASS
►PASS: Protocol, ADRs, Analysis report
• Risk Management system, activities ►Risk management plan (RMP)
• Distribution of Direct to healthcare ►Direct to Healthcare professional
professional communication Communication
• Training ►Respond to any query from EPVC
regarding safety
48
Thank you
49
3rd National Pharmacovigilance & Risk Management Conference
29-30 May 2013
Dubai, UAE
THE NEW EU PHARMACOVIGILANCE

LEGISLATION: IMPLEMENTATION AND
BEYOND
New PSUR - the PBRER

What you need to Know?
Shelley Gandhi
Director - Pharmacovigilance and Drug Safety
NDA Regulatory Science
© NDA Group 2013 1

Disclaimer
o The views and opinions expressed in the following PowerPoint slides are those
of the individual presenter.
o These PowerPoint slides are the intellectual property of the individual presenter
and are protected under the copyright laws of the United States of America and
other countries.
© NDA Group 2013 2

Topics to be covered
o Background – The importance of the PSUR

o History
o Latest developments
o Main Changes
o Timelines
o Overview of new format
o PRAC Assessment
o Conclusions
© NDA Group 2013

Background to new legislation provisions
o New EU Pharmacovigilance (PV) Legislation – 2 July 2012
 Regulation (EU) no. 1235/2010 of 15 Dec 2010
 Amends, as regards pharmacovigilance of medicinal products for human
use, Regulation (EC) 726/2004
o Directive 2010/84/EU of 15 Dec 2010

 Amends, as regards pharmacovigilance, directive 2001/83/EC relating to
medicinal products for human use
o Effective from 2/21 July 2012

 Transitional arrangements from July 2012 to 2015
o Implementing Regulation was published in the Official Journal on 20 June

2012, details on operation aspects of new legislation
http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:159:0005:0025:EN:PDF
© NDA Group 2013 4

Good Vigilance Practice (GVP) Modules
o These Modules are finalised and replace Vol 9A guidance.
MODULE I - Pharmacovigilance Systems and their

Quality Systems
MODULE II - Pharmacovigilance System Master File
MODULE III - Pharmacovigilance Inspections
MODULE IV - Audits
MODULE V - Risk Management Systems
MODULE VI -Management and Reporting of Adverse
Reactions to Medicinal Products
MODULE VII - Periodic Safety Update Reports
MODULE VIII - Post-Authorisation Safety Studies
MODULE IX - Signal Management
MODULE XV – Safety communication
o Send questions to QandA-PV-legislation@ema.europa.eu
© NDA Group 2013 5

PSUR – A critical document
o PSURs monitor the development of the safety profile of a

medicinal product after it has been placed on market, including an
integrated re-evaluation of the risk-benefit balance.
o In order to facilitate PSUR processing and evaluation- it is

important to develop common format and content
o Many aspects of a Pharmacovigilance (PV) system impact on the

ability of a MAH to produce compliant PSURS.
o Therefore, quality of PSURs provides a good indication of the

overall state of a MAH’s PV system.
© NDA Group 2013

History of the changes to PSUR
o Move towards Benefit-risk evaluation. MAHs move to new PSUR –
create template
o Clients to consider the requirements for PSURs in the context of other

additional pharmacovigilance risk-minimisation activities such as risk-
management plans and post-authorisation safety studies
key documents were released

o ICH E2C closed – step 4 Q4 2012 Agreed
o Final GVP published on 25 June 2012 Now being revised
o Implementing Measure – Final PSUR table of contents
o EURD list agreed by PRAC, CHMP, CMD – April 2013 Published 1
October – updated monthly.
o New PSUR format and content to be used from 10 January 2013
o Move submission cycle to 70 days
o Single assessment for NAPs 2015
o Prepare new template & Assessment will involve PRAC
© NDA Group 2013 7

PSUR – context in EU
o Format of PSUR shall follow structure in Implementing Regulation
o GVP module VII provides guidance on the preparation, submission

and assessment of PSURs
http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:159:
0005:0025:EN:PDF
o Scope, objectives, format and content of PSUR are described in
section B of module
o Required Format and Content for PSURs in EU are based for those on
PBRER described in the ICH guideline – E2C(R2)
o The PBRER replaces the PSUR format previously described in ICH-

E2C (R1).
o In EU , the report shall be described and named as PSUR
© NDA Group 2013 8

Content of PSUR Article 34 of IR
o PSUR is based on all available data & shall focus on new information which
has emerged from last data lock point
o Provide an accurate estimate of population exposed to medicines ( Sales
and prescriptions). Need to also show actual vs. sold calculation based on
Drug Utilisation studies
o Must contain the results of assessments of the effectiveness of risk
minimisation activities relevant to benefit and risk
o No Line listings needed – but must provide case narratives in the relevant
risk evaluation section of PSUR where integral to the scientific evaluation of
a signal or safety concern
o Based on cumulative safety data and benefit risk analysis MAHs must draw
conclusions to whether product information and RMP needs updating
o Clear guidance* on single active substance and all routes, indications,
dosage forms etc. – One PSUR
o Single vs. fixed combination separate PSUR and cross refer or provide
within one of the single actives
* unless specified on EURD list
© NDA Group 2013 9
PSURs – Format and Content.
o The PSUR format is proposed in modular structure which is intended to
minimise duplication with other documents such as DSUR and RMP. (Common
modules with RMP identified in GVP guideline)
o PSUR should focus on scientific assessment and summary information from all
data sources (incl. information from post-marketing studies or CTs in
unapproved indications)
o The main objective is to present a critical analysis of the benefit-risk balance

taking into account new emerging information in the context of what was known
previously. It should contain cumulative data while retaining focus on new
information that raised during the reporting period.
o The benefit risk evaluation should be undertaken in the context of on-going risk
management to facilitate optimisation of the benefit-risk balance through
effective risk minimisation measures.
© NDA Group 2013

What is staying the same & what is improved?
Staying Same
o A single report for an active substance
o Use of International Birth date (IBD) and Data Lock Point (DLP)
o Compatible with variable reporting frequencies
o Most of existing data presentation sections remain the same
o Summary tabulations remain
New and Improved

o Overview of safety signals and their evaluation
o Overview of benefits and benefit evaluation
o Integrated benefit-risk evaluation
o Strengthened link with risk management planning
o Cumulative data
o Supports lifecycle approach to continuous benefit-risk evaluation
© NDA Group 2013 11

Do we need to submit a PSUR?
o Waives the obligation to submit PSURs routinely for generic

medicinal products (authorised under DIR Art 10(1)), well-
established use medicinal products (authorised under DIR Art
10a), homeopathic medicinal products (authorised under DIR
Art 14) and traditional herbal medicinal products (authorised
under DIR Art 16a), [DIR Art 107b(3)]. (List has been published)
o For such products, PSURs shall be submitted where there is a

condition in the marketing authorisation or when requested by a
competent authority in a Member State on the basis of concerns
relating to pharmacovigilance data or due to the lack of PSURs
for an active substance after its authorisation [DIR Art
107b(3)(a) and (3)(b)]
o Frequency of submission determined in the Marketing

Authorisation

How should a PSUR be scheduled for submission?
o Marketing authorisation holders for products authorised before 02

July 2012 (centrally authorised products) and 21 July 2012
(nationally authorised products) and for which the frequency and
dates of submission of PSURs are not laid down as a condition to
the marketing authorisation or determined otherwise in the list of
Union reference dates shall submit PSURs according to the
following submission schedule [REG 28(2), DIR Art 107c(2)]:
o at 6 months intervals once the product is authorised, even if it

is not marketed;
o once a product is marketed, 6 monthly PSUR submission
should be continued following initial placing on the market in
the EU for 2 years, then once a year for the following 2 years
and thereafter at 3-yearly intervals.

What are the timelines for a PSUR submission?
o Marketing authorisation holders should submit PSURs to the Agency
according to the following timelines:
 Within 70 calendar days of the data lock point for PSURs covering
intervals up to 12 months (including intervals of exactly 12 months); and
 Within 90 calendar days of the data lock point for PSURs covering
intervals in excess of 12 months
 The timeline for the submission of ad hoc PSURs requested by
competent authorities will normally be specified in the request,
otherwise the ad hoc PSURs should be submitted within 90 calendar
days of the data lock point
(Changed from 60 to 70 or 90 calendar days post data lock point)
o Refer to list of Union Reference dates to determine submission frequency
o Electronic submission via EMA portal
o If your PSUR cycle specified in your MA does not match EURD list-vary MA
14
PSUR submission - transition
o During the transitional phase (i.e. until 12 months after the establishment of the
functionalities of the PSUR repository has been announced by the Agency
2013)
o MAHs shall submit the periodic safety reports to the Agency and all Member
States in which the medicinal product has been authorised or according to the
submission requirements of Members States which shall be published on the
Agency website.
o One year following establishment of the PSUR repository……
o MAHs will submit electronic periodic safety update reports only to the Agency.
Further changes to technical requirements for submission of electronic PSURs
shall be published by the Agency and shall take account of pre-standards and
standardisation work.
© NDA Group 2013

PSUR Format and Content
o The required format and content of PSURs in the EU are based

on those for the Periodic Benefit Risk Evaluation Report
(PBRER) described in the ICH-E2C(R2) guideline
o The PBRER replaces the PSUR format previously described in

the ICH-E2C(R1)
o As the PSUR should be a stand–alone document based on

cumulative data; summary bridging reports and addendum
reports, introduced in ICH-E2C(R1) guideline, will not be
accepted.
(Contd…)

PSUR Format and Content (Contd)
o Modular approach with overlap between PSUR, RMP and DSUR.
o Recital 23 of Directive 2010/84/EU newly establishes that the
obligations imposed in respect of PSURs should be proportionate to the
risks posed by medicinal products. PSUR reporting should therefore be
linked to the RMPs of a medicinal product (Module V).
o More emphasis on cumulative data and benefit “PSUR should focus on
summary information, scientific safety assessment and integrated
benefit-risk evaluation”
o Include individual case narratives only if relevant to scientific analysis of
a signal/safety concern
o Increased medical input and review required as these will be available
for analysis in the EudraVigilance database to support single EU
assessments.
o Line Listings not routinely required
 May be required by other regions
17
How to Present Case Narratives in a PSUR?
o Case narratives shall be provided in the relevant risk evaluation

section of the PSUR where integral to the scientific analysis of a
signal or safety concern [IR Art 34(4)].
o In this context, the term “case narratives” refers to clinical

evaluations of individual cases rather than the CIOMS
narratives. It should not be necessary to provide the actual
CIOMS narrative text included in the individual case safety
report (ICSR) but rather a clinical evaluation of important or
illustrative cases in the context of the evaluation of the safety
concern/signal.

Cumulative & Interval Summary tabulations from
Post-Marketing Data Sources
These should all be presented in a single table with interval and
cumulative data side by side.
o Serious and Non-serious reactions from spontaneous sources

o Serious ADR from non-interventional studies
o Serious ADR from other non-interventional solicited sources

PSUR Sections
• Executive Summary • Non-Clinical Data
• Introduction • Literature
• WWMAH Status • Other Periodic Reports
• Regulatory Actions Taken for Safety • LOE in Controlled Clinical Trials
Reasons • Late Breaking Information
• Changes to RSI • Overview of Signals: New,
• Estimated Use & Exposure Ongoing or Closed
Patterns • Signal and Risk Evaluation
• Cumulative & Interval • Benefit Evaluation
exposure in Clinical Trials • Integrated Risk Benefit
and Post-Marketing Analysis for Authorised
• Data in Summary Tabulations Indications
• Summary of Significant • Conclusions
Findings from Clinical Trials • Appendices
• Findings from Non-
Interventional Studies
• Information from Other Clinical
Trials & Sources
20
Revised Section: Risk-Benefit Evaluation
o Overview of signals: new, ongoing or closed
o Signal and risk evaluation
 Summaries of safety concerns
 Signal evaluation
 Evaluation of risks and new information
 Characterisation of risks
 Effectiveness of risk minimisation (if applicable)
o Benefit evaluation
 Important baseline efficacy and effectiveness information
 Newly identified information on efficacy and effectiveness
 Characterisation of benefits
o Integrated benefit-risk analysis for authorised indications
 Benefit-risk context – Medical need and important alternatives
 Benefit-risk analysis evaluation
Please note that this sections should be consistent with RMP, if there is one
available for the product.

Principles for the evaluation of the risk-benefit
balance
o The analysis of the R/B balance should incorporate an evaluation of the
safety, efficacy and effectiveness information that becomes available
during the reporting interval in the context of what was known previously.
o The risk evaluation should be based on all uses of the medicinal product,
including off-label use.
o If use of the medicinal product is identified where there are critical gaps
in knowledge for specific safety issues or populations, such use should
be reported in the PSUR (e.g. use in paediatric population or in pregnant
women). Sources of information on use outside authorisation may
include drug utilisation data, information from spontaneous reports and
publications in the literature.
o The scope of the benefit information should include both clinical trial and
real world data in authorised indications.

Principles for the evaluation of the risk-benefit
balance
The evaluation should involve:
o Critically examining information to identify new signals, leading to identification of new
potential or identified risks or contributed to knowledge of previously identified risks.
o Critically summarising relevant new safety, efficacy & effectiveness information that could
have an impact on the risk-benefit balance of medicinal product.
o Conducting an integrated benefit-risk analysis for all authorised indications based on the
cumulative information available since the development international birth date (DIBD),
the date of first authorisation for the conduct of an interventional clinical trial in any
country. For the cases where the DIBD is unknown or the marketing authorisation holder
does not have access to data from the clinical development period, the earliest possible
applicable date should be used as starting point for the inclusion and evaluation of the
cumulative information.
o Summarising any risk minimisation actions that may have been taken or implemented
during the reporting interval, as well as risk minimisation actions that are planned to be
implemented.
o Outlining plans for signal or risk evaluations including timelines and/or proposals for
additional pharmacovigilance activities

Overview of signals: new, ongoing or closed
o Recognised identified or potential risk where the new information suggests a
clinically significant difference in the severity or frequency of the risk
o Identified risk for which a higher frequency or severity of the risk is newly found
in an indicated subpopulation
o Identified risk which warrants a new warning, precaution, a new
contraindication or restriction in indication(s) or population or other risk
minimisation activities
o An ongoing signal refers to a signal that was still under evaluation at the DLP.
A closed signal refers to a signal for which an evaluation was completed during
the reporting interval. Signals that are both newly identified and closed during
the reporting interval should be handled as closed signals. (Tabulation of
signals ongoing and closed during interval: template provided, appendix
to PSUR)
o The detailed signal evaluations should be included in sub-section “Signal
evaluation” while the high level overview of signals should be provided in this
section
o Evaluation of new information in relation to any previously known risks and not
considered to constitute a newly identified signal should be provided in the
PSUR sub-section “Evaluation of risks and new information”
Signal and Risk Evaluation
o Do not duplicate information from previous sections. Only provide

interpretation and critical appraisal with a view towards characterising the
profile of those risks assessed as important or prompting regulatory action
(e.g. labeling changes)
o It is not necessary to include individual case narratives in the evaluation
sections of the PSUR but where integral to the scientific analysis of a signal
or risk, a clinical evaluation of important or illustrative cases should be
provided
o Summary of Safety Concerns
 Products with RMP – common section
 Products with no RMP – “important identified, potential risks and missing
information associated with use of the product, e.g. important AEs,
interactions, medication errors, pharmacological class effects”
o Signal Evaluation
 Signals that have been categorised as potential/identified risk, including
LOE
 Signals that have been rejected as false signals.
 Provide a description of each signal evaluation and the basis for the
decision………(Contd.)

Signal and Risk evaluation(Contd)
o Evaluation of Risks and New Information

 Interpretation of new information during the ‘reporting
interval’ with a view towards characterising the risk profile
 New information on important and not important identified

& potential risks
 Update on important missing information
o Characterisation of Risks
 Based on ‘cumulative data’
o Effectiveness of Risk Minimisation

 Should be consistent with RMP
26
Overview of Signals is included
o PSUR looking at benefit-risk and cumulative.
o Need an overview of signals: new, on-going, or closed - VII.B.5.15
o The purpose of this section is to provide an overview of signals detected, under review,
and evaluated during the reporting interval. The scope includes signals detected from
any source (for example from spontaneous reports, published literature, clinical trials,
epidemiological study findings) using quantitative and/or qualitative methods
o It should be noted that a safety signal is not synonymous with a statistic of
disproportionate reporting as a validation step is required
o Appendix 2 – Tabular summary
Signal Date Status Data Source Reason for Method of Action(s)
term detected (new, on- closed or Evaluation signal taken or
going or (for trigger and evaluation planned
closed) closed of summary of
signals) signal key data

Benefit Evaluation
o Important baseline efficacy and effectiveness information
 Summary of information on both efficacy and effectiveness of the medicinal
product at the beginning of the reporting interval only for authorised indication
 When multiple indications, populations, and/or routes of administration, the benefit
should be characterised separately by these factors when relevant
 When there have been no significant changes in the benefit or risk profile of the
medicinal product in the reporting interval, the summary should be succinct,
essentially the content of the reference information or included in the indications
listed in the Introduction section of the PSUR
o Newly identified information on efficacy and effectiveness

 E.g.. vaccines, anti-infective agents or other medicinal products where changes in
the therapeutic environment may impact on efficacy/effectiveness over time
o Characterisation of benefits
 Provide an integration of the baseline benefit information and the new benefit
information that has become available during the reporting interval, for authorised
indications

Integrated benefit-risk analysis for authorised
indications
o The marketing authorisation holder should provide in this PSUR

section an overall appraisal of the benefit and risk of the
medicinal product as used in clinical practice.
o This section should provide an analysis and integration of the

information in the previous sections with respect to benefit and
risk and should not duplicate the benefit and risk information
presented in sections “Signal evaluation”, “Evaluation of risks
and new information” and “Characterisation of benefits”

Revised Section: Clinical Trials
o More extensive clinical study information required

 List of Post-authorisation safety studies required as
appendix to PSUR
o PSUR section: Summaries of significant findings from clinical
trials during the reporting interval (some important sub-sections are as below)
 New clinically important information regarding safety and

efficacy from on-going and completed trials
 Long-term use, especially for gene therapy, cell therapy &
tissue engineered products)
 New safety data related to fixed combination therapies
 Lack of efficacy in controlled clinical trials, especially for life
threatening conditions
30
PRAC involvement in Assessment of PSURs
o Will cover all aspect of risk management and use of medicines

including detection, assessment, minimisation and communication of
risk and will consider this in the therapeutic context of the use of the
medicine and the design and evaluation of PASS and PV audit
o PRAC will
o Agree and monitor RMPs
o Supervise the design and evaluation of PASS
o Agree Additional Monitoring requirements and be involved in
assessment of removal process at 5 years
o Responsible for initial prioritisation and analysis of signals and
where necessary agreement of the appropriate risk minimisation
measures and communications.
o Review PSURs starting with CAP products
o Review safety issues at CHMP request
o Minutes in public domain

PSUR Assessment
o Review process involving the PRAC and opportunity for MAH to comment
 Single assessment
 Timelines set out
o Competent authorities in the Member States shall assess PSURs to determine
whether there are new risks or whether risks have changed or whether there are
changes to the risk-benefit balance of medicinal products [DIR Art 107d]
o The EU single assessment can include joint assessment for medicinal products
authorised through either national or centralised procedures for marketing
authorisation. The Agency shall make available a list of Union reference dates
and frequency of submission [REG Art 26(g)] which will be legally binding
o The Agency shall make the PSURs available to the competent authorities in
Member States, members of the Pharmacovigilance Risk Assessment
Committee (PRAC), of the Committee for Medicinal Products for Human use
(CHMP) and of the Coordination Group for Mutual Recognition and
Decentralised Procedures - Human (CMDh) and the European Commission by
means of a PSUR repository [DIR Art 107b(2)]
o It is the responsibility of the competent authority in the Member State to
evaluate PSURs for purely nationally authorised medicinal products. The
assessment of the PSUR is conducted in accordance with the national
legislation

CAP PSUR assessment at PRAC
1. EMA Validation – appoint PRAC rapporteur (liaise with CHMP rapp)

2. Retrieval of case data from EudraVigilance
3. PAR sent out after 60 days
4. By day 90 (PRAC members and MAH send comments to Agency and
PRAC Rapp)
5. Update AR sent about Day 105
6. Oral Explanation can be at request of PRAC or MAH in case of
o A revocation or suspension of MA
o A new contraindication
o A restriction to indication
o Or a recommendation to reduce dose
7. PRAC will then adopt AR with recommendations for MA at next meeting
(update to SmPC, RMP, conduct PASS, review BR, close monitoring etc)
8. Major recommendations sent to CHMP for adoption

PSUR assessment process
o In the case of an assessment that recommends any action, the
CHMP shall, within 30 days of receipt of the report by the PRAC,
consider the report and adopt an opinion including a timetable for the
implementation of the opinion.
o Where the opinion of the CHMP differs from the recommendation of

the PRAC, the CHMP shall annex to its opinion a detailed
explanation of the scientific grounds for the differences together with
the recommendation.
o The final recommendations, opinions and decisions shall be made

public by means of the European medicines web-portal.
© NDA Group 2013

PSUR Assessment Procedure for Centrally
Authorised Product
Receipt of PSUR(s) from MAH(s)
Technical Validation by the Agency

Article 28 of
Start Regulation (EC)
60 days No 726/2004
Rapporteur Preliminary Assessment Report
30 days
Comments from MAH & members of the PRAC
15 days Oral Explanation

Rapporteur Updated Assessment Report
At next PRAC Meeting
If regulatory action is recommended
PRAC Recommendation rec’d by CHMP

30 days
CHMP Opinion with timetable for implementation
Opinion sent to EC, MAH & NCAs
EC decision to update Centralised MA
End

PRAC January 2013 Minutes- PSURs
o Amifampridine – FIRDAPSE (CAP) -Evaluation of a PSUR procedure

o Regulatory details:
o PRAC Rapporteur: Julie Williams (UK)
o Background
o Amifampridine is a voltage-dependent potassium channels blocker used to treat the
symptoms of Lambert-Eaton myasthenic syndrome (LEMS) in adults.
o Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk
balance of Firdapse, a centrally authorised medicine containing amifampridine, and
issued a recommendation on its marketing authorisation.
o Summary of recommendation(s) and conclusion
o Based on the review of the data on safety and efficacy, the risk-benefit balance of
Firdapse (amifampridine) in the approved indication(s) remains favourable.
o The PRAC recommended the maintenance of the current terms of the marketing
authorisation.
o The frequency of submission of PSURs should remain 6-monthly and the next
PSUR should be submitted to the EMA within 70 days of the data lock point.

Important Points to consider
o Significant change to submission, format and content

 Implications on company processes, templates, database,
and tracking (Aggregate Reports Calendar)
o MAH should consider cross-functional processes
o Develop in-house template linked to definition to what you as a

company will place in each section
37
Quality systems for PSURs
o An appropriate quality system should be in place in order to avoid failure to comply with
PSUR requirements such as:
 non-submission: complete non-submission of PSURs, submission outside the correct
submission schedule or outside the correct time frames (without previous agreement
with the competent authorities);
 unjustified omission of information required;
 poor quality reports: poor documentation or insufficient information or evaluation
provided to perform a thorough assessment of the new safety information, signals, risk
evaluation, benefit evaluation and integrated benefit-risk analysis, misuse not
highlighted, absence of use of standardised medical terminology (e.g. MedDRA) and
inappropriate dismissal of cases with no reported risk factors in cumulative reviews;
 submission of a PSUR where previous requests from competent authorities (worldwide)
have not been addressed.
o Any significant deviation from the procedures relating to the preparation or submission of
PSURs should be documented and the appropriate corrective and preventive action should
be taken. This documentation should be available at all times
o When the preparation of the PSUR is delegated to third parties, the MAH should ensure that
they are subject to a quality system compliant with the current legislation. Explicit
procedures and detailed agreements should exist between the MAH and third parties. The
agreements may specifically detail the options to audit the PSUR preparation process

PSURs - transition
o New assessment for CAPs involving PRAC from July 2012
o Does every PSUR assessed by PRAC from July go to CHMP? Only

where regulatory action i.e. variation, suspension or revocation of the
MA is adopted by PRAC then this must be sent to CHMP
o If PRAC adopts a recommendation on the maintenance of the MA

procedures ends with PRAC
o In time EMA will process all reports for the EU (new database and
tracking tool required)
o In time all assessments will come through the EMA Committees

(including all the nationally authorised products)
o If PSUR submitted before 2 July then only CHMP involved if after then
PRAC will review

In summary – the new PSUR arrangements
o EMA to set up and maintain a repository for PSURs and the

corresponding assessment reports so that they are fully and
permanently accessible….when will this be ready 2013?
o PSURs to become an analysis of the risk-benefit balance of a medicinal

product rather than a detailed listing of individual case reports already
submitted to the EudraVigilance database……MAHs must demonstrate
continuous signal detection with training needs in benefit-risk
assessment
o The CHMP or the coordination group shall, following the consultation

with PRAC, either approve or deny requests to change the dates or the
frequency of submission of PSURs and this shall be made public by the
Agency. …CHMP and PRAC must work together
© NDA Group 2013

Activities for preparing a PSUR
o Focus should be on:

 Preparation and monitoring the schedule for submission (PSUR
calendar)
 Format of the PSUR
 Allocation of responsibilities
 Collection of the information
 Analysis of data
 Evaluation of data
 Compiling the PSUR and presentation
 Submission and distribution

© NDA Group 2013
Conclusions
o New PSUR provides more comprehensive information on benefits

and risks
o Encourages the integration of signal detection, risk management

processes with benefit risk evaluation
o Risk Based submission requirements
o Legally binding outcome so changes to product information are

consistent
o Recommendations in public domain via PRAC assessment

Glossary
o CAT-Committee for Advanced Therapies o MA- Marketing Authorisation
o CMDh – Coordination Group for Mutual o MAH – Marketing Authorisation Holder
Recognition & Decentralised Procedure – o MedDRA – Medical Dictionary for
human Regulatory Activities
o CHMP - Committee for Medicinal Products o MS – Member State
for Human Use o PAES-Post Authorisation Efficacy study
o COMP-Committee for Orphan Medicinal o PASS – Post-authorisation Safety Studies
Products o PDCO-Paediatric Committee
o EC – European Commission o PRAC – Pharmacovigilance and Risk
Assessment Committee
o EMA – European Medicines Agency o PSMF – Pharmacovigilance System Master
o ENCePP – European Network of Centres for File
Pharmacoepidemiology and o PSUR – Periodic Safety Update Report
Pharmacovigilance o PV - Pharmacovigilance
o EU – European Union o QPPV – Qualified Person responsible for
Pharmacovigilance
o EURD list – List of European Union
Reference Dates and frequency of o RMP – Risk Management Plan
submission of Periodic Safety Update o SAWP-Scientific Advice Working Party
Reports o WPs- Working Parties
o GVP – Good Pharmacovigilance Practices
o ICSR - Individual Case Safety Reports

Questions?
Thank you for listening
shelley.gandhi@ndareg.com
© NDA Group 2013

PASS and PAES
Professor Saad Shakir

MB ChB LRCP&S FRCP FFPM FISPE MRCGP
Director – Drug Safety Research Unit, UK
Post Authorisation Safety Study
PASS
Any study relating to an authorised

medicinal product with the aim of identifying,
characterising or quantifying a safety
hazard, confirming the safety profile of the
medicinal product, or measuring the effectiveness
of risk management measures
PASS
• The supervision of PASS will be the
responsibility of PRAC
– Non-interventional
– Initiated, managed or financed by MAH
– Full outside Directive 2001/20/EC (Clinical
Trial Directive)
Pharmacovigilance Risk Assessment Committee
(PRAC)
initial and updated RMPs

initial prioritisation and analysis of signals
appropriate risk minimisation measures
including communications
protocols for and results from non-
interventional PASS
have input into all safety referrals
Post-authorisation safety studies
(PASS)
Any study relating to an authorised medicinal
product conducted with the aim of identifying,
charactersing or quantifying a safety
hazard,confirming the safety profile of a medicinal
product or of measurement of risk management
measures
PASS
General principles
• Characterise the safety profile
• Provide assurance about absence of a
safety concern
• Investigate potential or identified risk, e.g. characterise the incidence
rate, estimate rate ratio or rate difference in comparison to non-
exposed population and investigate risk factors and effect modifiers
• Evaluate the risks of a medicinal product used in authorised
indications by patient groups not studied in the pre-authorisation
phase (e.g. pregnant women, elderly patients)
• To assess patterns of utilisation and use of the medicinal product
that may have an impact on its safety (e.g. co-medication,
medication errors)
• To evaluate the effectiveness of risk minimisation activities
PASS
• The supervision of PASS will be the
responsibility of PRAC
– Non-interventional
– Initiated, managed or financed by MAH
– Full outside Directive 2001/20/EC (Clinical
Trial Directive)
PASS
• At first authorisation
• Post-authorisation
PASS is a condition of the authorisation and is legally binding
In the event that the safety concern applies to more than one
medicinal product, the EMA/National Competent Authority shall
… encourage the MAHs to conduct a joint post-authorisation
safety study.
Post authorisation Efficacy Studies
PAES
• At authorisation: “where concerns related to some
aspect of the efficacy of the product are identified or can
be revealed only after the product has been marketed”.
• Post authorisation: “when the understanding of the
disease or the clinical methodology indicate that the
previous efficacy evaluations have to be modified
significantly”.
• EU Commission may adopt implementing measures
regarding situations when PAES may be required.
• EMA shall adopt scientific guidelines (not expected
before end of 2012).
S Strauss
Legal basis for PAES
Directive 2010/84/EC
• “Such studies may be aimed at collecting data to enable
assessment of safety or efficacy of medicinal products in
everyday medical practice.”
• “To conduct post-authorisation studies where concerns
relating to some aspects of the efficacy of the medicinal
product are identified and can be resolved only after the
medicinal product has been marketed.”
• “ To conduct a PAES when the understanding of the
disease or the clinical methodology indicate that
previous efficacy evaluations might have to be revised
significantly.”
Scenarios for PAES might be:
• Effectiveness studies or studies with increased external

validity
• Outcome studies following initial evaluation on
– biomarkers/surrogate
– endpoint
• Studies in sub-populations
• Long-term/sustained efficacy
• Products with narrow benefit/risk
EMA conducted a public consultation in Spring 2012
A Spooner
Strengthened legal basis in the new
legislation
To require post authorisation studies for:
• Safety
• Efficacy
It is necessary from a public health perspective to complement
the data available at the time of authorisation with additional
data about the safety and, in certain cases, efficacy of
authorised medicinal products.
Competent authorities should therefore be empowered to

impose on the MAH the obligation to conduct
post-authorisation studies on safety.
Principles of oversight
• Submit the protocol and progress reports
• Send final report within 12 months of the
end of data collection*
• Any information from the study which
might influence the evaluation of the
risk/benefit balance of the product
* Unless written waiver has been granted
Transparency
• The study protocol and the abstract of the final
study report should be public to ensure
transparency
• Public electronic record of studies
• Protocol must be entered prior to data collection
• Updated when substantial amendments are
made
Are the new regulations a step in the right
direction regarding improving the role of
PASS studies in RM?
Yes in many ways. They will improve studies with
poor standards
But unlikely will have an effect on good quality studies, for the
new legislation will have no affect on:
– The inherent problems of bias, confounding and missing information
– Limited availability of new drugs after licensing because of cost
effectiveness requirements
– Suitable comparators?
Post authorisation efficacy studies
• Guidelines needed, consultation underway

• Long established products - how medicines die
(regulation vs. clinical practice), e.g. alpha
methyl dopa
• However, now medicines will die when
unfavourable benefit risk
• Long established products when the efficacy
was established with different levels of rigour
Post authorisation efficacy studies
• Outcome studies, comparative

effectiveness
Effectiveness vs. efficacy
• While the argument that effectiveness is
complementary to efficacy is strong, there are
issues about reproducibility; in some cases you
“can get the result you want”.
• Handling the results is easy when efficacy and
effectiveness are consistent, but can be difficult
and possibly contentious if they don’t
• Transparency is necessary, but more (far more)
methodology research is needed
Effectiveness of risk minimisation
Science base – move up in the
hierarchy
Science based – move up in the hierarchy
• Arguments about the relative importance of different

kinds of evidence are an unnecessary distraction. What
is needed instead is for "investigators to continue to
develop and improve their methodologies; for decision
makers to avoid adopting entrenched positions about the
nature of evidence; and for both to accept that the
interpretation of evidence requires judgement."
Michael Rawlins – The Harveian Oration RCP London 2008

• Arguments about the relative importance of different

kinds of evidence are an unnecessary distraction. What
is needed instead is for "investigators to continue to
develop and improve their methodologies; for decision
makers to avoid adopting entrenched positions about the
nature of evidence; and for both to accept that the
interpretation of evidence requires judgement."

• Randomised controlled trials (RCTs), long regarded as the 'gold standard' of

evidence, have been put on an undeserved pedestal. Their appearance at
the top of "hierarchies" of evidence is inappropriate; and hierarchies,
themselves, are illusory tools for assessing evidence. They should be
replaced by a diversity of approaches that involve analysing the totality of
the evidence-base.
• Arguments about the relative importance of different kinds of

evidence are an unnecessary distraction. What is needed instead is
for "investigators to continue to develop and improve their
methodologies; for decision makers to avoid adopting entrenched
positions about the nature of evidence; and for both to accept that
the interpretation of evidence requires judgement."

• Randomised controlled trials (RCTs), long regarded as the 'gold standard' of

evidence, have been put on an undeserved pedestal. Their appearance at
the top of "hierarchies" of evidence is inappropriate; and hierarchies,
themselves, are illusory tools for assessing evidence. They should be
replaced by a diversity of approaches that involve analysing the totality of
the evidence-base.
• Arguments about the relative importance of different kinds of

evidence are an unnecessary distraction. What is needed instead is
for "investigators to continue to develop and improve their
methodologies; for decision makers to avoid adopting entrenched
positions about the nature of evidence; and for both to accept that
the interpretation of evidence requires judgement."

Workshop:
Case Studies on how to design
studies for Risk Management
Professor Saad Shakir

MB ChB LRCP&S FRCP FFPM FISPE MRCGP
Director – Drug Safety Research Unit
Product for weight reduction
• Product to assist loosing weight
• Novel central pharmacological action
• In clinical development important ADRs;
depression, suicidal ideation
• Time to onset not clear
• Unclear if those affected had history of
depression/suicidal ideation
New controlled release formulation of an
atypical antipsychotic
• Immediate release formulation has been on the
market for nearly 10 years
• Relatively safe; as with atypical antipsychotics
main ADRs in SmPC are:
• EPS but less frequent than typical antipsychotics
• hyperglycaemia and type 2 diabetes but less frequent than
some other atypical antipsychotics
• drowsiness and sedation
• CR formulation maximum dose 800 mg/day, IR
600 mg/day and more rapid dose escalation
Regulatory concerns
• Short term effects of CR (higher maximal
dose and more rapid dose escalation)
• EPS, sedation and metabolic syndrome.
Rapid release buccal formulation of an
opiate for breakthrough pain in cancer
• IR and transdermal formulations have
been on the market for a number of years
• Concerns are:
– respiratory depression (rare and early) – more
frequent in patients with risk factors, e.g.
COPD
– Misuse
– Recreational use
– Accidental misuse by children

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The Egyptian Pharmacovigilance

Medicines are safe! (X)

Approved medicines are safe! (X)

No medicine is safe! (X)

No medicine is without risk! (√)

• “Pharmacovigilance is the science and activities relating to the

• Continuously Monitoring medicines to determine unrecognized

• Continuously Re-assessing the risks and benefits of medicines,

Risk Mgt. Signal Detection

Preclinical Clinical trial Market authorization Clinical practice

Clinical Drug Safety

Post Marketing Surveillance

*Post marketing surveillance10

*Absorption, distribution, metabolism, 11

Healthy Open trial, not

Very common ≥10/100

Common (Frequent) 1/100 -10/100

Uncommon (Infrequent) 1/1000-1/100

Very rare <1/10,000

• Small number of patients studied

 Pharmacovigilance is needed in every country because of

 Pharmacovigilance is needed for all drugs including generics

 Forgotten part of the

►Humanitarian concerns: Hippocratic oath “First Do No

ADVERSE EFFECTS US study 1994

4th – 6th cause of death

• Lazarou et al JAMA 1998; 279:1200-1205

• Cascade of Released regulations and legal framework.

‫ﺗﺸﻜﻴﻞ ﺍﻟﻤﺠﻠﺲ ﺍﻷﻋﻠﻰ ﻟﺮﺻﺪ ﺍﻷﺛﺎﺭ ﺍﻟﺠﺎﻧﺒﻴﺔ ﻭ ﺍﻟﻤﻨﺎﻭﺋﺔ ﻟﻸﺩﻭﻳﺔ‬

Marketing Authorization Holders Health Care Professionals

Tentative Licenses Final licenses

Human medicines, Medical Cosmetics Veterinary

Dark blue: Full members

Hospitals Start Relevant ADR Irrelevant ADR

Private Clinics Regulatory

Drafting plans, timelines,

Stakeholder communication &

 Drafting plans, timelines, guidelines & SOPs

Red Bullets: initiated not finished

 More awareness for MAHs & HCPs

UAE – MOH DUBAI 2013 1

UAE – MOH DUBAI 2013 2

Drugs : first cause

> 1000 hepatotoxic drugs

VARIETY OF LIVER DISEASES

UAE – MOH DUBAI 2013 4

UAE – MOH DUBAI 2013 5

• Cholestatic (rare) : increase of over 2 ULN in

• Mixed (frequent) : both ALT and ALP are

Navarro NEJM 2006

UAE – MOH DUBAI 2013 7

UAE – MOH DUBAI 2013 8

Chronic liver diseas

UAE – MOH DUBAI 2013 9

̶ Sources of information are multiple

̶ Target populations may be different across the world

̶ Medical practices may be different from a country to an

There is a need of investigating cases in an homogeneous