Diapositive 1

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CLINICAL ASSESSEMENT OF ANTIVENOM Past and
current situation
J.-P. CHIPPAUX
IRD, Paris, France
2
Discovery of antivenoms February 10th, 1894
Phisalix
Calmette
MNHN Paris
IP Paris
First clinical use 1895 In Vietnam
3
HISTORY OF ANTIVENOM
200 BC
Mithridate VI
Adaptation to poison
1887
Sewall
Animal immunization with venom
1888
Roux-Yersin
Experimental transfer of immunity
1890
Behring-Kitasato
Clinical transfer of immunity
1894
Phisalix
Experimental antivenom
1895
Calmette
Clinical use of antivenom
1901-7
Global diffusion of antivenom
1924
Ramon
Toxoid preparation
1930
Felton
IgG precipitation
1936
Pepsin digestion
70s ?
Clinical pharmacological studies
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Etiology of envenoming and mortality
Incidence
Mortality
Snakes
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GLOBAL BURDEN OF SNAKEBITE
No venomous snakes
Few
Low
High
Average
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INCIDENCE AND SEVERITY OF SNAKEBITES
730 M people 5,000 SB 5 Deaths
340 M people 5,000 SB 5 Deaths
3650 M people 1,5 M SB 60,000 Deaths
350 M people 40,000 SB 50 Deaths
580 M people 100,000 SB 600 Deaths
650 M people 500,000 SB 25,000 Deaths
30 M people 1,500 SB 500 Deaths
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EPIDEMIOLOGICAL DATA AVAILABLE FOR AFRICA
National and local representative surveys
Limited household and hospital surveys
Limited hospital surveys
No data
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EPIDEMIOLOGY OF SNAKEBITE IN AFRICA
High incidence and mortality Poor epidemiological
information
High diversity of venomous snakes Variability and
complexity of venoms
Difficulties in management of snakebite Treatment
seeking behavior and scarcity of health centers
Difficulties in treatment of envenoming Formation
of health workers and accessibility of AV
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TREATMENT SEEKING BEHAVIOR
1. Therapeutic choice

25 Nigeria 40 Bénin 60 Kenya 80
Sénégal 80 Guinée
Do not reach health center
2. Delay for treatment

Admission time 24 h. Benin 12 h.
Cameroon 48 h. Nigeria
Average delay
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DELAY OF TREATMENT
m
Cameroun
50
Benin
Togo
60
40
50
30
40
30
20
20
10
10
0
4
8
12
16
20
24
0
m
4
8
12
24
gt 24
m
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ASSESSMENT OF ANTIVENOM QUALITY
In vitro tests provide
An evaluation of the efficacy
A probability of tolerance
But are insufficient to guarantee identical
results in human cases
Clinical studies are essential
To confirm clinical effectiveness and safety
To improve the clinical use of AV
For registration before use in man
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DEFINITION AND TYPES OF CLINICAL STUDIES
Anecdotal clinical studies (ACS) reports of
isolated cases
Observational clinical studies (OCS) analysis
of case series
Non randomized comparative clinical studies
(CCS) comparison of AV or procedures
Randomized clinical trials (RCT) high
methodological standards
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CLINICAL ASSESSMENT OF AV General frame
4 formal phases with distinct objectives resulting
in different methods

Phase I safety-pharmacology ( 5-10 healthy
subjects/group)
RCT
Phase II efficacy, dosage ( 30-60
patients/group)
RCT CCS
Phase III validation for registration ( 100-200
patients/group)
All types
Phase IV post marketing studies, improvement (
100-1000 patients per group)
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PURPOSES OF CLINICAL STUDIES

Effectiveness
Safety - tolerance
Dosage
Pharmacology
Symptomatic and adjuvant treatments
Administration routes
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BASIC METHODS OF OCS
Objective
Descriptive - Analytical
Comparison type
No comparison
Formal presentation
No
1. Retrospective (descriptive) study
Fast and Inexpensive Limited description
2. Prospective (comprehensive) study
Time consuming and expensive Precise description
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OBSERVATIONAL CLINICAL STUDIES
Snake 1
Snake 7
Snake 6
Snake 2 Scorpion 2
Snake 7
Snake 3 Scorpion 1
Snake 4 Spider 1
Snake 30 Scorpion 3 Spider 1 Total 34
Antivenom 33 (97)
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DESCRIPTION OF OCS
Global (34)
Africa ME (11)
Method Prospective Retrospective
18
6
5
5
Product AV Symptomatic
33
11
1
0
Animal Snake Scorpion Other
30
9
3
2
1
0
Purpose Efficacy Tolerance Dosage Other
23
7
14
5
1
5
0
2
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BASIC METHODS OF CCS
Objective
Descriptive - Analytical
Comparison type
Case/control or historical or ad hoc
Validity
External
Test/control group
Regular cases
Comparability groups
No
Decision criteria
Multiple
Analysis
Intention to treat
Statistical risks
a 5
Formal presentation
No
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NON RANDOMIZED COMPARATIVE CLINICAL STUDIES
Snake 3
Snake 1
Snake 4 Scorpion 6
Snake 1 Scorpion 4
Snake 2
Snake 3
Snake 1
Snake 15 Scorpion 10 Total 25
Antivenom 21 (84)
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DESCRIPTION OF CCS
Global (25)
Africa ME (7)
Method Prospective Retrospective
8
3
17
4
Product AV Symptomatic
21
7
1
0
Animal Snake Scorpion Other
15
3
10
4
0
0
Purpose Efficacy Tolerance Dosage Other
21
6
4
0
3
6
1
2
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RANDOMIZED TRIALS
Aims to compare the effects of a treatment in the
patients
Controlled trial Only the treatment
differs between the compared groups
Before the treatment ? Randomization
Blind Identical procedures
During the treatment ?
Validity of control Statistical analysis
After the treatment ?
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BASIC METHODS OF RCT
GS RCT
Pragmatic RCT
Objective
Explicative
Management
Comparison type
H0 H1 or H0 ? H1
H0 ? H1
Validity
Internal
External
Test/control group
Selective cases
Regular cases
Comparability groups
Identical (procedures/blind)
No, after random
Validity of control
Placebo or reference product
No
Decision criteria
Unique
Multiple
Analysis
IT or PP
IT
Statistical risks
a 5 and ß 20
a 5
Standard presentation
Yes (CONSORT)
No
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VALIDITY OF THE CONTROL
Treatment action
Known level of control Known level tested AV
Tested antivenom
d2
?
Reference antivenom
d1
? or d
Placebo
? n
No treatment
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RANDOMIZED CLINICAL TRIALS
Snake 1
Snake 21
Scorpion 2
Snake 4
Snake 12 Caterpillar 1
Snake 1 Spider 3 Ant 1
Snake 39 Others 7 Total 46
Antivenom 33 (72)
Placebo or reference product 13 (28)
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DESCRIPTION OF RCT
Global (46)
Africa ME (6)
Method Blind Open
16
2
31
4
Product AV Symptomatic
33
5
14
1
Animal Snake Scorpion Other
39
4
2
2
5
0
Purpose Efficacy Tolerance Dosage Other
36
6
9
0
9
0
4
0
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Clinical assessment Current situation
Since 1970, 105 clinical studies
Snake 84 Scorpion 15 Other animals 6
Concerning AV 86 clinical studies
Observational clinical studies 33
Non randomized clinical studies 21
Randomized clinical trials 32
Africa ME 24 clinical studies
Snake 16 Scorpion 8
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Clinical studies in Africa and Middle East Snake
Antivenoms (24)
OCS 11 - Prospective 6 -
Retrospective 5
CCS 7 - Prospective 3 -
Retrospective 4
RCT 6 - Blind 2 - Open 4 - 1-ß
lt 20 2 - 20 lt 1-ß lt 80 4
Efficacy 19 Tolerance 5 Dosage 4 Other 1
Placebo or reference product 2 (8)
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Conclusion (1)
Clinical studies necessary for ultimate
validation of AV
Clinical studies necessary for registration
Importance of methodology
Necessity of simple and precise criteria
Ethical and legal obligations
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Conclusion (2)
Objectives Efficacy / Tolerance / Dosage
Comparability of groups before and during
intervention
Validity of control product placebo or
reference product
Simple and clear criteria (and design)
Relevant statistical analysis
Standardized presentation of the results
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Thanks