VICH Task Force for Efficacy
Studies for Combination
Products
Progress Report for the 32th SC /6th VOF meeting (Final)
Introduction
 At the 3rd VOF meeting in Nov 2013, China PR presented a Concept
Paper for a VICH guideline on “efficacy studies for combination drug
products”.
 The SC & VOF members welcomed the proposal confirming that it is an
important topic where guidance is currently lacking.
 The scope of this topic is very broad and could lead to several GLs.
 It would be useful to identify the different combinations available in
order to reach agreement on which GLs should be developed.
The SC decided to create a task force (TF) chaired by JMAFF.
Mandate for TF
 To elaborate a discussion paper
proposing a more focused scope
for the development of a VICH GL
for efficacy studies for combination
products.
<<< Concept paper from China
 The TF will
 Prioritize the target products >Explore Major combination
 Explore the possibility of
a general policy document >Analyse GLs already in Place
TF members
VICH
members
Observer
VOF
members
Additional
contributors
JMAFF (chair)
K. Noda
JVPA
E. Oishi
IFAH-EU
M. Bobey
EU
K. Healey
US FDA
C. Groesbeck
AHI
B. McKusick
South Africa, Nat. Dept. health
V. Naidoo
China PR, IVDC
S. Xu
Argentina, SENASA
L. Sbordi
Taiwan, Council of Agriculture
T-R. Jan
UEMOA
K.Th. Domagni
CAMEVET
L. Sbordi
Australia, APVMA
P. Reeves
NZ, Min. Primary Industry
W. Hughes
Part 1
Major Combination
How to categorize the products?
Code
Categorization elements
Antiparasitics
Antimicrobials
Anthelmintics
AP-Hl
Antiprotozoals
AP-Pr
Ectoparasiticides
AP-Ec
Endectocides
AP-EnEc
Other Antiparasitics
AP-X
Antibacterials
AM-Bc
Antimycotics
AM-Mc
Antivirals
Intramammary
antibacterials
Other Antimicrobials
AM-Vr
AM-IM-Bc
AM-X
Anti-inflammatories
AI
Antiseptics
AS
Disinfectants
DI
(others, if any)
X
Major combination-products
VICH members
Combination-category
IFAHJMAFF JVPA
EU
US FDA AHI
EU
AP-Hl
1
1
1
1
1
AP-Pr
1
AP-Ec
1
1
1
1
AP-EnEc
1
1
1
1
1
AP-Hl
AP-Pr
1
1
AP-Hl
AP-Ec
1
AP-Hl
AP-EnEc
AP-Hl
AP-x
1
AP-Hl
X
AP-Ec
AP-x
AP-EnEc
AP-x
AM-Bc
1
1
1
1
1
AM-Mc
AM-Vr
AM-IM-Bc
1
1
AM-Bc
AM-Mc
AM-IM-Bc
AM-Bc
AM-Bc
AM-Mc
AI
AM-Bc
AI
AM-Bc
AI Analgesics
AP-Pr
Hormones
AI
AS
AS
DI
DI
Vitamins
Vitamins
Minerals
Gastrointestinal
Hormones
Cardiology
X
Total / legislation
Total / member status
1
1
1
1
1
Observer
S.Africa Asust.
1
1
1
1
1
1
NZ
ChinaPR
1
1
1
1
1
1
1
1
1
1
1
1
VOF members
Argentina/
Sub- Total
Taiwan UEMOA
CAMEVET
total
1
9
1
4
1
7
1
7
2
2
37
1
1
2
1
1
1
1
1
1
10
0
0
16
5
0
1
1
1
1
1
1
4
1
1
7
1
AM-Bc
AM-Bc
1
1
1
2
1
2
1
1
1
1
1
1
2
2
1
1
1
1
1
1
1
1
1
1
1
10
1
4
1
1
10
10
45
6
5
7
10
20
1
3
5
7
4
16
0
81
15
2
1
1
1
1
1
1
2
2
1
81
Major Combination-products
40
35
30
25
20
15
10
5
0
APs
AMs
AM+X
AI
AS
AS+DI
DI
Vit
Combination-category
Vit+Min Gastr
Horm Cardiol
X
Combination
category
AP-HI
AP-Pr
Ingredients
Number of
Country/Region
Abamectin +Derquantel
1
Abamectin +albendazole +selenium +cobalt
1
Albendazole +closantel,
1
Emodepside +Praziquantel
3
Fenbendazole +levamisole,
1
Fenbendazole+Praziquantel
1
Febantel+pyrantel
1
Febantel +Praziquantel +Pyrantel
5
Ivermectin +Clorsulon
2
Ivermectin +closantel
1
Ivermectin+pyrantel
1
Levamisole +Abamectin,
1
Levamisole +Albendazole,
1
Levamisole +closantel +albendazole +abamectin,
1
MilbemycinOxime+praziquantel
1
Moxidectin+triclabendazole
1
Oxfendazole +Levamisole,
1
Amprolium +ethopabate,
1
Amprolium +Ethopabate +Sulfaquinoxaline
2
Dinitolmide+glycarbylamide
1
Pyrimethamine+sulfadimethoxine
1
Combination
category
AP-Ec
AP-EnEc
Ingredients
Number of
Country/Region
Amitraz+Fipronil+(S)-methoprene
Amitraz +cypermethrin,
Amitraz+Metaflumizone
Betacyfluthrin +piperonyl butoxide,
Cipermethrin+ethion
Cymiazol +cypermethrin,
Diazinon +pyriproxyfen,
Dicyclanil +diflubenzuron,
Dinotefuran+permethrin+pyriproxyfen
Fipronil+cyphenothrin
Fipronil+(S)-methoprene
Fipronil+permethrin
Imidacloprid+flumethrin
Imidacloprid+moxidectin
Imidacloprid +permethrin,
Imidacloprid+permethrin+piperonyl butoxide
Indoxacarb+permethrin
Pyrethrins +piperonyl butoxide
Abamectin +levamisole,
Abamectin +praziquantel,
Closantel+ivermectin
Closantel+mebendazole,
Clorsulon+Ivermectin
Eprinomectin+fipronil+praziquantel+(S)-methoprene
Fluazuron +ivermectin,
Imidacloprid+Ivermectin,
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Imidacloprid+Moxidectin,
Ivermectin+Pyrantel
Ivermectin+Praziquantel,
3
2
2
Milbemycin+Spinosad
1
MillbemycinOxime+Lufenuron
MilbemycinOxime+Lufenuron+Praziquantel
3
2
MilbemycinOxime+spinosad
1
Combination
category
AP-Hl
AP-Pr
AP-Hl
AP-Ec
AP-HI
AP-EnEc
AP-HI
X
AP-Hl
AP-x
AP-Ec
AP-x
AP-EnEc
AP-x
Ingredients
Number of
Country/Region
Emodepside+toltrazuril
1
Emodepside+praziquantel
Fipronil+methoprene+amitraz
Ivermectin+albendazole
Narasin+nicarbazin
Levamisole HCI +praziquantel,
Levamisole HCI +oxyclosanide,
Albendazole +closantel,
Levamisole HCI +rafoxanide,
Levamisole +Sodium Selenate,
Albendazole +Sodium Selenate,
Abamectin +Sodium Selenate,
Levamisole +Disodium Cobalt EDTA,
Albendazole+praziquantel
fenbendazole+praziquantel+pyrantel
MilbemycinOxime+lufenuron,
MilbemycinOxime+lufenuron+Praziquantel
Moxidectin + imidacloprid,
Ivermectin + closantel,
abamectin+Ivermectin
clorsulon+Ivermectin
Ivermectin+nitroxinil
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Specific consideration #1
 The EU member insisted not to include AM combination as a target
category, supported by other countries.
 Regulators do not wish to encourage new developments of AM
combination.
 A VICH GL on such combination products could be misunderstood as
encouragement for their development.
Specific consideration #2
 Antimicrobial agents and coccidiostats for “growth/ feed
efficiency promotion” is regulated under the “feed safety
legislation” rather than “pharmaceutical legislation” in Japan.
 Some antiseptics (AS) and an antiprotozoal (AP-Pr) are not within
the remit of VMP authority in Australia.
 Chemicals used in animal barn and/or fish preserve may be
regulated under “environmental legislation” in some countries.
Currently outside the reach of VICH
Part 2
Guidelines in Place
Guidelines/Guidance in Place
Item
#1
Title
Product
Category
Guidance on pharmaceutical fixed
combination products
General
(EMEA/CVMP/83804/05)
#2
#3
#4
Questions and answers on the
CVMP guideline on fixed
combination products
(EMEA/CVMP/83804/2005)
AP
Type of document
Technical requirement guideline
Additional document to #1
European Legislation
(EU Directive 2001/82/EC ),
(p16)Art 13b
General
Legal basis for #1 and #2
CVM GFI #24 Drug Combinations
for Use in Animals
General
Technical requirement guideline
#5
WAAVP guideline:
Anthelmintic combination products
targeting nematode infections of
ruminants and horses
AP
Technical requirement guideline
#6
Australian Pesticide and Veterinary
Medicine Agency: Preamble for
WAAVP guideline: Combination
anthelmintic products for ruminants
and horses
AP
Statement adopting #5 WAAVP
GL as National GL
Technical Requirement GLs in Place
Item
#1
Title
Guidance on
pharmaceutical
fixed combination
products
Category
Scope
General
EU data requirements for efficacy, safety
and residues documentation for veterinary
medicinal products, containing 2 or more
active substances.
General
Information and data to demonstrate that
the combination of drugs provides a
benefit that cannot be obtained by the use
of each of the drugs individually
#4
CVM GFI #24 Drug
Combinations for
Use in Animals
#5
•
•
WAAVP guideline:
Anthelmintic
combination
products targeting
nematode infections
of ruminants and
horses
AP
•
A scientific basis for the approval
Anthelmintic products with two or more
constituents with similar spectra of
activity from different pharmacological
classes
For use in addition to the existing
requirements/GLs for single-API
products.
Structure –General GLsParts
Introductory
part
#1: EMEA/CVMP/83804/05
 Introduction (background)
 Scope
 Legal Basis
Discussion
part
 Justification of the Combination
 Interactions
 Indications
 Potential Advantages
• Improvement of activity
• Broadening of the activity spectrum
• Use of a combination product versus
combined use of single substances
 Risk-Benefit assessment
Dossiers
Requirements
part
 General requirements
 New fixed combination products
 Combination products that meet the
criteria for well established use
 Combination products that meet the
criteria for generic application
 Specific Requirements
 Safety and residues documentation
 Preclinical and clinical documentation
(Preclinical data, Dose-finding, Tolerance,
Clinical data, Resistance, Exceptions)
#4: FDA/ CVM GFI #24
 Introductory statement






Non-Interference
Rational
Titration
Ranges
General Efficacy
Combination Claims and
Treatment Comparisons
(very in detail)
Structure –AP GL –
Parts
Introductory part
Discussion part
#5: WAAVP/Australia
 Introduction (general)
 Combining anthelmintics: current situation
 Objectives of the anthelmintic combination guideline
 Rationales for the use of anthelmintic combination products
• Managing existing resistance
• Delaying anthelmintic resistance
• Specific targeting of dose-limiting species
• Maximizing breadth of spectrum
 Concerns about fixed-dose anthelmintic combination products
• Drug–drug interactions
• Common mechanisms of resistance
• Best-practice management of combination anthelmintics
Dossiers
Requirements
part
 Justification for the combination
 Dose determination data on the anthelmintic constituent actives in the
combination
 Target animal safety and pharmacokinetic data showing noninterference and acceptable safety
 Product bioequivalence
 Dose confirmation studies
 Field efficacy studies
Conclusion
 General combination GL
 EU(#1) and US(#4) are the representative General GLs.
 Internationally harmonized GL by extracting appropriate
elements from them.
 Specific combination GL
 Main target : Anti-Parasitics
 Drug resistance control will be a main objective.
 Inclusion of WAAVP(#5)GL into VICH framework should be
explored in collaboration with the Anthelmintics-EWG.
 Other specific combination may be a target in the future.
 After some experiences
 Further discussion by the VOF and SC members needed
Mission
Completed
Thank you
感謝