History and Progress of Pharmacovigilance, Significance of Safety Monitoring, Pharmacovigilance in India And International Aspects, WHO International Drug Monitoring Programme, WHO and Regulatory Terminologies of ADR, Evaluation of Medication Safety, Establishing Pharmacovigilance Centres in Hospitals, Industry and National Programmes Related to Pharmacovigilance, Roles and Responsibilities in Pharmacovigilance, International Non-Proprietary Names for Drugs, International Classification of Diseases, Passive and Active Surveillance, Comparative Observational Studies, Targeted Clinical Investigations and Vaccine Safety Surveillance, Aris G Pharmacovigilance, VigiFlow, Statistical Methods for Evaluating Medication Safety Data

1. PHARMACOVIGILANCE
Department of Pharmaceutical Sciences, Maharshi Dayanand University,
Rohtak (124001)
Submitted To; Submitted By;
Dr. Govind Singh Mr. Deepak Kumar
Assistant Professor Roll no. 1831
(Pharmacology) M. Pharm. 2nd Sem. (Pharmacology)
1

2. History and Progress of Pharmacovigilance
2

3. 3

4. 4

5. 5

6. Pharmacovigilance Programme of India (PVPI) was launched in July 2010.
Goal:
• To ensure that the benefits of use of medicine outweighs the risks and thus safeguard the
health of the Indian population
Objectives:
• To monitor Adverse Drug Reactions (ADRs) in Indian population
• To create awareness amongst health care professionals about the importance of ADR
reporting in India
• To monitor benefit-risk profile of medicines
• Generate independent, evidence based recommendations on the safety of medicines
Pharmacovigilance Programme of India (PVPI)
6

7. Objectives:
• Support the CDSCO for formulating safety related regulatory decisions for
medicines
• Communicate findings with all key stakeholders
• Create a national centre of excellence at par with global drug safety monitoring
standards
Pharmacovigilance Programme of India (PVPI)
7

8. Programme Governance - PvPI
8

9. Steering
Committee
Strategic
Advisory
Committee
SignalReviewPanel
CoreTrainingPanel
QualityReviewPanel
MINISTRY OF HEALTH & FAMILY WELFARE (MOHFW)
Central Drugs Standards Control Organisation
(CDSCO)
Drugs Controller General of India (DCGI)
Pharmacovigilance Programme of India
(PVPI) –
National Coordinating Centre (NCC)
All India Institute of Medical Sciences
(AIIMS), New Delhi
M O N
C
I
E
A
T
N
D
O
T
R
R
R
I
E
N
S
G
NORTH,
Ghaziabad
SOUTH,
Chennai
EAST,
Kolkata
WEST,
Mumbai
CDSCO ZONAL CENTRES
GOVERNANCE STRUCTURE - PVPI
PHARMA
INDUSTRY
Immunization
Programs
9

10. 10

11. Roles & Responsibilities of the Functional Units
Pharmacovigilance Programme of India
• Collection of ADR reports
• Follow up of ADR reports, check completeness for a valid case, causality assessment
• Data entry – Vigiflow
• Monthly reports to National Coordinating Centre at AIIMS
• Training/sensitization/ feedback to physicians/ students/patients
ADR Monitoring
Centre
• Review completeness, Quality Check, Causality Assessment, transmit ADRs to Vigiflow
• Training to ADR Monitoring centres
• Feedback to the ADR Monitoring centres
• Educate and inform medical community via MEDICINE SAFETY NEWSLETTER
• Consult Signal Review Committee
• Reporting to DCGI Office
National
Pharmacovigilance
Coordinating
Centre at AIIMS
• Provide administrative support to the ADR Monitoring Centres
• Report to DCGI (CDSCO)
Zonal CDSCO
Centres
• Report to DTAB (Ministry of Health & Family Welfare)
• Formulate and communicate safety related regulatory decisions for medicines
CDSCO
11

12. 40 PvPI AMCs
National Coordinating Center,
AIIMS, New Delhi
4 Zonal CDSCO Offices
(provide operational and logistical support)
Ghaziabad Mumbai Kolkata Chennai
PvPI Headquarters, CDSCO
Pharmacovigilance Programme of India (PVPI)
PHASE 1 12

13. The centres included in the first wave of the Programme - 12 13

14. Steering Committee - PvPI
MEMBER SECRETARY
Assistant Drug Controller, New Delhi,
India
14

15. Monitoring and Evaluation of Medication Safety Data
Process
Indicators
• No. of AMCs participating in the PvPI
• No. of AMC personnel trained in a year
• Funds budgeted for PvPI & actual spent
• AMC personnel working full time for PvPI
Outcome
Indicators
• Software platform established
• No. of ADR reports received in a year
• No. of ADR reports processed in a year
• No. of ADR reports submitted to Vigiflow
Impact
Indicators
• No. of signals generated & confirmed
• No. of safety related alerts issued by CDSCO
15

16. Pharmacovigilance Centres
• It is a centre of expertise for the art
and science of monitoring and
analysis of drug. It should be set up
with the approval of the authority
responsible for the regulation of
medicines ("regulatory authority").
• Its functions within the regulatory
authority, a hospital, an academic
institution or as an independent
facility such as a trust or
foundation.
16

17. Basic Steps in Setting up a Pharmacovigilance Centre
• Make contacts with the health authorities and with local, regional or national
institutions and groups, working in clinical medicine, pharmacology and toxicology
outlining the importance of the project and its purposes.
• Design a reporting form and start collecting data by distributing it to hospital
departments, family practitioners, etc.
• Produce printed material to inform health professionals about definitions, aims and
methods of the pharmacovigilance system.
• Create the centre: staff, accommodation, phone, word processor, database
management capability, bibliography etc.
• Take care of the education of pharmacovigilance staff with regard, for example, to:
• data collection and verification
• interpreting and coding of adverse reaction descriptions
• coding of drugs
• case causality assessment
• signal detection
• risk management
17

18. • Establish a database (administrative system for the storage and retrieval of
data)
• Organize meetings in hospitals, academia and professional associations,
explaining the principles and demands of pharmacovigilance and the
importance of reporting.
• Promote the importance of reporting adverse drug reactions through medical
journals, other professional publications, and communications activities.
• Maintain contacts with international institutions working in
pharmacovigilance, e.g. the WHO Department of Essential Drugs and
Medicines Policy (Geneva) and the Uppsala Monitoring Centre, Sweden.
18

19. Financial Requirements
INFRASTRUCTURE
HUMAN
RESOURCE
COMUNICATION OPERATIONAL
EXPENSES
19

20. Capacity Building Model
20

21. Infrastructure
LOCATION EQUIPMENT DATABASE
21

22. Human Resources
22

23. Budget
23

24. Reporting Database
Vigibase Online
• It is web-based reporting software solution
for pharmacovigilance centre. This software
allows seamless electronic transmission of
reports within a country
• This web makes possible improved
communication between prescriber and
pharmacovigilance centres.
24

25. Focused ADR monitoring watchlist
CRITERIA
• Restriction/Withdrawal by any other regulatory agency in the world
• Reports in media
• Adverse reports published in WHO Newsletters
• Diseases of public health importance in relation to Indian population
• Drugs, Vaccines for Epidemics/Pandemics
• Signals generated from the spontaneous reports received under the PvPI
25

26. Proposed drugs for focused ADR monitoring
1. Oseltamivir
2. Letrozole
3. Nimesulide
4. Pioglitazone
5. Rosiglitazone
6. Tegaserod
7. PPA
8. Gatifloxacin
Concerns about drug
safety in other countries
Absent/ Minimal safety
data from India
Proactive & focused
ADR
monitoring in
dedicated
pharmacovigilance
centres
Regulatory
action based
on Indian AND
global data
26

27. Seamless synergistic pharmacovigilance partnership
Pharmacovigilance
Patient Policy makers
(regulators)
Physician and
medical
associations
Public Press (media)
Pharmaceutical
Industry and
associations
27

28. ACADEMIA
INDUSTRY REGULATOR
28

29. Potential for synergy
• 289 medical colleges and 282 dental colleges
• More than 837 Pharmacy colleges
• More than 657 recognized nursing colleges (B.Sc and M.Sc)
• Over 600 pharmaceutical companies (IDMA members)
• CDSCO, WHO, ICMR, other affiliates
• MCI, DCI, PCI, Consumer associations etc.
29

30. International Non Propriety Name for Drugs
• Drugs are generally marketed by their brand names though there is a legal
requirement to mention generic names in the labels. Countries have their own
systems of generic nomenclature for pharmaceutical substances. However owing to
the various languages used by different national nomenclature systems, there is a
need to have a uniform standardized system of generic names that are accepted
worldwide, which would help in identifying the composition of a pharmaceutical
substance.
• The WHO administers an international generic nomenclature system called INNs also
known as rINN, for recommended International Nonproprietary Name or pINN for
proposed International Nonproprietary Name).
• International Nonproprietary Names (INN) facilitates the identification of
pharmaceutical substances or active pharmaceutical ingredients. Each INN is a
unique name that is globally recognized and is public property. A nonproprietary
name is also known as a generic name.
30

31. The INN System and its Aim
• Initiated in 1950 by a World Health Assembly resolution
• Began operating in 1953
• Cumulative list of INN now stands at some 7000 names designated since that time
• 120-150 new INN.
• To provide health professionals with a unique and universally available designated
name to identify each pharmaceutical substance.
• For the clear identification, safe prescription and dispensing of medicines to patients,
and
• For communication and exchange of information among health professionals and
scientists worldwide.
• Nonproprietary names are intended for use in pharma, labeling, product information,
advertising and other promotional material, drug regulation and scientific literature,
and as a basis for product names, e.g. for generics.
31

32. Trade Names and Non Proprietary Names
• Most products available on the market are nowadays advertised, promoted, and
identified by a trade name. In pharmaceutical field, trade names are used when
prescribing, dispensing, selling, promoting, or buying a medicament. Trade names are
usually selected by the owner of the product and registered in national trademark or
patent offices. They are private property and can be used only with the consent of the
owner of the trademark.
• In most cases brand names are chosen for a finished pharmaceutical product. Therefore,
pharmaceutical preparations containing the same active drug substance are frequently
sold under different brand/trade names, not only in different countries, but even within
the same country.
• Various trade names for one substance (example: paracetamol)
• Nonproprietary names are intended to be used as public property without restraint.
These names are usually designated by national or international nomenclature
commissions.
• Nonproprietary names are designations to identify the active pharmaceutical drug
substance rather than the final product.
• The selection of a nonproprietary name follows established rules so that the name itself
communicates to the medical and pharmaceutical health professional to which the active
drug substance belongs.
32

33. Selection of INN
• The names which are given the status of an INN are selected by the World Health
Organization on the advice of experts from the WHO Expert Advisory Panel on the
International Pharmacopoeia and Pharmaceutical Preparations.
• The process of INN selection follows three main steps:
-a request/application is made by the manufacturer or inventor
-after a review of the request a proposed INN is selected and published for
comments;
- after a time-period for objections has lapsed, the name will obtain
the status of a recommended INN and will be published as such if no objection
has been raised. Since the name is available in the public domain it may be
used freely. However, it should not be registered as a trade-mark since this
would prevent its use by other parties.
33

34. How?
• INN is designated for the active part of the molecule only, to avoid the multiplication
of entries in cases where several salts, esters, etc. are actually used. In such cases, the
user of the INN has to create a modified INN (INNM).
• Ex: mepyramine maleate (a salt of mepyramine with maleic acid)
• The primary principles for selection:
• Distinctive in sound and spelling;
• Not too long; and
• Not liable to confusion with other names in common use.
• Ex: ac: anti-inflammatory agents, ibufenac derivatives
• -coxib for COX-2 inhibitors, a type of anti- inflammatory drugs (e.g. celecoxib)
• Do not select names for mixtures of substances.
• Do not select for herbal substances (vegetable drugs) or for homoeopathic products.
• Do not select names for those substances that have a long history of use for medical
purposes under well-established names such as those of alkaloids (e.g. morphine,
codeine), or trivial chemical names (e.g. acetic acid). 34

35. Use of INNs in India
• In India, Section 13 (b) of the Trade Marks Act, 1999 prohibits the registration of
names of chemical elements or INNs which have been declared by the World Health
Organization (WHO) and notified by the Registrar of Trade Marks. Nevertheless, there
are reported incidents of marketing of drugs under names that are similar to INNs.
The WHO has brought the same to the attention of the Drug Controller General of
India. The basic requirement of Section 13 (b) of the Trade Marks Act, 1999 is that
INNs must be notified by the Registrar.
• The use of INNs as trademarks constitutes a problem in two ways: use of parts of
INNs in trademarks can dilute the INN system by creating confusion in drug
nomenclature. Secondly, since trademarks enjoy legal protection unlike INNs, the use
of INN stems in trademarks may thwart the coining of new INNs in the future using
the common stem, where a trademark owner opposes the INN. This is because in the
selection of INNs it is ensured that the rights of trademark owners are not affected
through INNs.
• Use of INNs to coin brand names
INN Stem Brand Name Company
Vinleurosine -osine Virosine DR Ranbaxy
35

36. International Classification of Disease
• International statistical classification of diseases and related health problems in short
“ICD” is the international standard diagnostic tool for epidemiology, health
management and clinical purposes.
• ICD is designed as health care classification system which provides the diagnostic
codes for classifying diseases including classification of wide variety of signs,
symptoms, abnormal findings, complaints, social circumstances and external cause
of injury or disease.
• This includes the analysis of the general health situation of population groups. It is
used to monitor the incidence and prevalence of diseases and other health
problems.
• It is used for reimbursement and resource allocation decision-making by countries.
36

37. Historical Synopsis
• In 1860, Florence nightingale →made first model of systemic collection of hospital
data.
• In 1893, French physician, Jacques Bertillon→ introduced Bertillon classification of
cause of death
• In 1898, American public health association→ recommended revision of ICD system
every 10 years.
• The revision followed minor changes until 6th version of ICD→ morbidity and
mortality condition and section on mental disorders
• WHO →responsibility for preparing and publishing the ICD revisions every 10 years.
• The ICD -10 was formed in 1893, as the Bertillon classification of international list of
causes of death.
• The work on ICD -10 started in 1983 → approved in 1990 at 43rd world health
assembly (WHA)
37

38. Classification
• Classification was as follow: Scientific approach was adopted in classifying diseases.
According to certain characteristics of diseases or injuries, such as
a) The part of the body affected
b) The etiologic agent
c) The kind of morbid change produced by the disease
d) The kind of disturbance of function produced by the disease or injury.
ICD
➢Certain infectious and parasitic diseases(A00-B99)
➢Neoplasm(C00-D48)
➢Diseases of the blood and blood forming organs and certain disorders
involving the immune mechanism(D50-889)
➢Endocrine, nutritional and metabolic diseases(E00-E90)
➢Mental and behavioral disorders(F00-F99)
➢Disease of the nervous system(G00-G99)
38

39. ➢ Endocrine, nutritional and metabolic diseases(E00-E90)
➢ Mental and behavioral disorders(F00-F99) Disease of the nervous system (G00-G99)
➢ Diseases of the eye and adnexa(H00-H59)
➢ Diseases of the ear and mastoid process(H60-H95)
➢ Diseases of the circulatory system (I00-I99)
➢ Diseases of the respiratory system(J00-J99)
➢ Diseases of digestive system(K00-K93) Disease of the skin and subcutaneous tissue
(L00-L99)Diseases of musculoskeletal system and
➢ connective tissue(M00-M99)Diseases of genitourinary system(N00-N99)
Material and Methods
• Pregnancy, childbirth and puerperium(O00-O99)
• Certain conditions originating in perinatal period(P00-P96)
• Congenital malformations, deformations and chromosomal abnormalities (Q00-Q990)
• Symptoms, signs and abnormal clinical and laboratory findings, not else where
classified (R00-R99)
• Injury, poising and certain other consequences of external causes (9S00-T98)
• External causes of morbidity and mortality(V01-Y90).
39

40. The ICD -10 is Arranged in 21 Major Chapters
1. Certain Infectious and parasitic diseases.[A00- B99]
2. Neoplasms [C00-D48]
3. Diseases of the blood and blood forming organs and certain disorders involving the
immune mechanism[D50 –D89]
4. Endocrine nutritional and metabolic diseases [E00-E90]
5. Mental and behavioral disorders [F00-F99]
6. Disorders of the nervous system [G00-G99]
7. Diseases of eye and adnexa [H00-H99]
8. Diseases of the ear and mastoid process [H60-H95]
9. Diseases of circulatory system [I00-I99]
10. Diseases of respiratory system [J00-J99]
11. Diseases of digestive system [K00-K99]
40

41. 12.Diseases of the skin and subcutaneous tissue [L00-L99]
13.Diseases the musculoskeletal system and connective tissue[M00-M99]
14.Diseases of genitourinary system [N00-N99]
15.Pregnancy , childbirth and puerperium [O00-O99]
16.Certain conditions originating in perinatal period [P00-P96]
17.Congenital malformations, deformations and chromosomal abnormalities
[Q00- Q99]
12.Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere
classified [R00-R99]
13.Injury, poisoning and certain other consequences of external causes [S00-T98]
14.External causes of morbidity and mortality [V01-Y98]
15.Factors influencing health status and contact with health services . [Z00-Z99].
ICD 11
➢ The world health organization is currently revising the ICD towards ICD-11.
➢ The development is taking place on an internet based workspace called " icat "
platform ,
➢ The draft of the ICD -11 system → submitted to WHO’s world health assembly
(WHA)→ by 2017 and a final version → in 2018.
41

42. Advantages and Limitations of ICD
Advantages Limitations
1. Fast aggregation of health data 1. Discussion is limited to classified diseases
2. To know the real time information about
current health situation
2. Common term descriptions of diseases
3. Wider analysis of community health 3. Covers the most common diseases
4. Global health assessment 4. Country specific modifications of certain
diseases
42

43. Surveillance
• Systematic ongoing collection, collation, and analysis of data and the timely
dissemination of information to those who need to know so that action can be
taken.
• Ongoing systematic collection, analysis, and interpretation of health data,
essential to the planning, implementation, and evaluation of public health
practice, closely integrated with the timely dissemination of these data to those
who need to know.
• Continuous analysis, interpretation, and feedback of systematically collected
health data, generally using methods distinguished by their practicality,
uniformity, and rapidity rather than by accuracy or completeness.
43

44. Passive Surveillance
• In Passive Surveillance, criteria are established for reporting diseases, risk factors
or health-related events. Health practitioners are notified of the requirements and
they report events as they come to their attention. This is the more common type
of surveillance
• Laboratories, physicians, or others regularly report cases of disease or death to
the local or state health department; e.g. A doctor’s office reports 2 cases of
measles, A nursing home reports an unusual number of older patients with
unexplained rashes
• Passive surveillance
➢Issue case definition
➢Wait for cases to be reported
44

45. Active Surveillance
• For Active Surveillance, criteria are established for reporting disease (or its
absence), risk factors or health events, but those maintaining the surveillance
system initiate reporting. Active surveillance is used when there is an indication
that something unusual is occurring. Using the example from above - if a health
department receives a case report for measles, a serious vaccine-preventable
disease, active surveillance will be triggered. Public health practitioners will actively
search for other cases, using a standard case definition: calling doctors' offices for
any cases, following up to find additional cases among those exposed, checking
laboratories.
• Active surveillance
• Go looking for cases
• E.g., MD offices, hospitals, pathology departments
45

46. Comparative Observational Studies
Comparative Observational Studies Traditional epidemiologic methods are a key
component in the evaluation of adverse events. There are a number of observational
study designs that are useful in validating signals from spontaneous reports or case
series. Major types of these designs are cross sectional studies, case-control studies, and
cohort studies (both retrospective and prospective)
• Cross-Sectional Study (Survey) - Data collected on a population of patients at a
single point in time (or interval of time) regardless of exposure or disease status
constitute a cross-sectional study.
• Case-Control Study - In a case-control study, cases of disease (or events) are
identified. Controls, or patients without the disease or event of interest, are then
selected from the source population that gave rise to the cases.
• Cohort Study - In a cohort study, a population-at-risk for the disease (or event) is
followed over time for the occurrence of the disease (or event). Information on
exposure status is known throughout the follow-up period for each patient.
46

47. Cross-Sectional Study (Survey)
47

48. Case-Control Study
48

49. Cohort Study
49

50. Aris Global
Step 1ST – Data Entry
50

51. Step 2 - Medical Coding
Medical coding is crucial and it is essential to ensure terms are coded consistently and
accurately. To facilitate case coding, ARISg has an integrated MedDRA browser that allows
fast and accurate coding.
Step 3 - Quality Assurance
The QA function is important to ensure that cases have been entered correctly and
accurately. Serious cases are often singled out for specific attention, but non-serious
cases are often routed to QA for review randomly. QA will independently review the case
against the available source documentation and will often assign a QA score, indicating
the quality of the case. ARISg fully supports the QA function, routing cases for QA review
based on company requirements and enabling the verification of the case score.
51

52. Step 4 – Medical Assessment
52

53. Step 5 - Case Distribution
Once a case has been identified as a reportable case, it needs to be distributed to
all affiliates,
authorities and other stakeholders such as investigators (see agXchange SIR
section described below).
Often this is a manual, time-consuming process as local and regional safety
officers review reports distributed to them from their head office. ARISg
eliminates this burden as the report distribution module identifies reports to be
distributed based on the report distribution rules of each recipient, also
identifying the type of report to be distributed (including blinded reports). Of
course, the E2B format is fully supported through agXchange ESM™, which also
allows users to configure an extended E2B format for partner exchange.
53

54. SIGNAL DETECTION, DATA MINING AND RISK MANAGEMENT PLANNING
54

55. COMPLIANCE TRACKING
55

56. Vigi Flow
Vigiflow is an Individual Case Safety Report (ICSR) management system developed and hosted
by Uppsala monitoring centre (UMC).
How to access Vigiflow?
1. Web address: https://adr.who-umc.org
2. Log in is done with a personal user name and password from the secure web-page.
The minimum information you have to enter on a spontaneous report for it to be
considered ‘complete’ by VigiFlow is the following six mandatory fields:
• 1) Report title
• 2) Patient initial
• 3) Patient age (either date of birth, age at time of onset or age group)
• 4) Onset date of reaction (year only)
• 5) Reaction term
• 6) Drug name 56

57. Patient Information
57

58. REPORT INFORMATION
58

59. Information on sender
59

60. Information on Primary Source
60

61. Death related information
61

62. Result of test and procedure
62

63. Relevant medical history and past drug therapy
63

64. SAVE REPORT
64

65. Statistical Evaluation of Drug Safety Data
• There has been growing awareness of the importance of statistical evaluation of
drug safety data
• Traditional statistical approaches for analyzing safety data are often descriptive
and perhaps oversimplified, and knowledge of and experience with proper
methods may be inadequate
• A well-planned, systematic, and consistent approach including use of
comprehensive statistical methods for assessing safety during drug development
is warranted
• There were numerous guidance documents issued from regulatory authorities in
the past decade.
65

66. Impact of AE Grouping on Statistical Analysis
• Signal detection and evaluation can be obscured by
• Lack of standard definition of AEs
• Lack of standard coding conventions and terminology usage
• Lumping and splitting of terms without prospective plans
• One of challenges that DMCs are generally facing in assessing safety during clinical
trials
• Grouping AEs into categories can pose statistical challenges
Broad vs Narrow Classification
• Historically, broad search is viewed as conservative in the sense that it minimizes
the risk of missing an event of interest.
• However, it can lead to non-differential misclassification and bias the relative risk
estimate towards null
• Treatment effect can be diluted
• Signal can be masked
66

67. Bayesian Applications in Safety Signal Detection
• Three-Tier System for Analyzing Adverse Events in Drug Safety Data
• Tier 1 AEs -- events for which a hypothesis has been defined
• Tier 2 AEs -- events that are not pre-specified and “common”
• Tier 3 AEs – events that are not pre-specified and infrequent
• Advantages of Bayesian Methods in Safety Signal Detection
• Bayesian hierarchical modeling provides a useful tool to address multiplicity by
explicitly modeling AEs with the existing AE coding structure
• Bayesian approach is attractive statistically in dealing with rare events
• Bayesian Methods Have Been Commonly Used for Signal Detection in Data from
Various Sources
• Clinical trial AE data and Spontaneous adverse drug reaction reports.
67

68. Meta-Analysis for Analyzing Safety Data
• Statistical Considerations for Meta- analysis of Safety Data Using RCTs
➢Scale of measures
➢Heterogeneity assessment
➢Fixed effect vs random effects models
➢Statistical methods for analyzing rare event meta- analysis
➢Individual patient data (IPD) meta-analysis
➢Multiplicity
68

69. Absolute Measure vs Relative Measure
Measure Pros Cons
Absolute measure • Easy to interpret;
• Always well defined so it
allows the inclusion of
studies with zero events
• Knowledge of absolute risks
is important in clinical
decision making
• Clinical importance
may depend on the
underlying baseline
event rate, but it is
less an issue for rare
events
Relative measure
• Typically analyzed in
logarithm scale; more stable
on average than absolute
measures
• Good statistical modeling
property
• Undefined when
control rate is zero,
so it does not allow
the inclusion of
studies with zero
events
69

70. Heterogeneity Assessment
• Clinical
• Patient selection (e.g., severity of disease)
• Interventions (e.g., duration, dosing, control)
• Outcomes (e.g., definitions of endpoints)
• Methodological, e.g.,
• Mechanism of randomization
• Allocation concealment
• Handling of withdrawals
• Statistical
• Numerical variability in results, beyond random error
• Graphical (e.g. forest plots)
• Statistical tests (e.g. Cochran’s Q with 2 test; I2 statistics)
70

71. Fixed‐effect vs. Random‐effects Models
• Fixed effect = common effect across all studies
• Inference is to the studies at hand
• Reasonable to expect (?) when designs and populations are similar across
studies
• Random‐effects models: true underlying population effects differ from study to
study and that the true individual study effects follow a statistical distribution
• The analytic goal is then to estimate the overall mean and variance of the
distribution of true study effects
71

72. Statistical Methods for RE Meta-analysis
• The choice of method in a sparse event meta-analysis is important since certain
methods perform poorly; especially when group imbalances exist
• Bias is greatest using the I-V and D-L methods, and M-H method with continuity
correction (CC) of 0.5
• The M-H method using the alternative CC provides the least biased results for all
group imbalances
• At event rates below 1%, the Peto method provides least biased , most powerful
estimate and best CI coverage for balanced groups but bias increases with greater
group imbalance and larger treatment effect
• Logistic regression performs well and generally unbiasedand reliable
• The Bayesian fixed-effect model performs consistently well irrespective of
group imbalance
• Alternative CCs perform better than a constant CC
72

73. Advantages of Individual Patient Data Meta analysis
• Enables to use common definitions, coding and cut- points, and produces
consistent analyses across multiple studies
– E.g., age categories may have been defined using different category boundaries
– Different threshold hemoglobin values may have been used to define
‘anemia’
• Allows specification of a common set of patient‐level covariates so subgroup
analyses across trials can be performed
• Permits the investigation of additional hypotheses (those related to
individual patient characteristics)
73

74. 74