Authorisation of antimicrobials in the EU
VICH Outreach Forum, February 2017
Presented by Nick Jarrett
European Medicines Agency
An agency of the European Union
Authorisation of antimicrobials in the EU
Overall goal:
•
Demonstrate quality, safety and efficacy of the veterinary medicinal product (as for
all veterinary medicinal products)
Specific goal:
•
Minimise potential for antimicrobial resistance and ensure antimicrobials retain their
effectiveness for treating microbial infections in humans - particularly relevant for
food producing animals
− evaluate the potential for resistance development
− ensure conditions of use are appropriate (indications and dosing regimen) and
advice to veterinarians is clear (conditions of use, risk mitigation measures)
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Authorisation of antimicrobials in the EU
Relevant VICH guidelines relevant to antimicrobial resistance
•
VICH GL36(R): Studies to evaluate the safety of residues of veterinary drugs in
human food: general approach to establish a microbiological ADI
–
•
•
Disruption of the colonisation barrier (not related to resistance)
•
Increase in the population of resistant bacteria in the human colon
VICH GL27: Guidance on pre-approval information for registration of new
veterinary medicinal products for food producing animals with respect to
antimicrobial resistance
–
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Focuses on potential for residues in food to impact on the human gastrointestinal
flora:
Focuses on the potential for antimicrobial drugs to lead to development of
resistant organisms in target animals, which could be transferred to
consumers via food
−
MICs against a wide variety of microorganisms
−
Information on resistance mechanisms, molecular genetic basis of resistance,
information on the occurrence or absence of transfer and rate of transfer of resistance
genes
Authorisation of antimicrobials in the EU
VICH GL36(R) and VICH GL27
Topics for discussion:
• Are MRLs (or equivalent) set locally or are standards set by external
countries/bodies (eg Codex Alimentarius) used?
• If MRLs (or equivalent) are set locally is impact on GI flora taken into account?
Is VICH GL36 used?
• Is VICH GL27 used as a basis for considering the potential for development of
resistance in the target animal?
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Authorisation of antimicrobials in the EU
Further guidance on assessment of resistance potential
While VICH GL27 describes the required data, it does not describe how these data
should be interpreted and incorporated into the risk assessment
•
Draft CVMP guideline on the assessment of the risk to public health from
antimicrobial resistance due to the use of an antimicrobial veterinary medicinal
product in food-producing animals
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500183774.pdf)
• CVMP guideline covers risk from direct contact with target animals as well as risk
associated with food of animal origin
Asks:
“What is the risk to public health from antimicrobial-resistant bacteria resulting from
the intended use of the proposed veterinary medicinal product?”
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Authorisation of antimicrobials in the EU
Further guidance on assessment of resistance potential
The risk assessment:
•
Hazard identification – seeks to identify antimicrobial resistant bacteria and resistance
determinants in foodborne bacteria that could be selected for due to use of the substance and
transferred to humans
•
Release assessment – looks at proposed uses of the product and asks whether the biological
conditions in the target animal will favour resistance development that may be “released”
(at slaughter or via direct contact)
•
Exposure assessment – considers likelihood of human exposure to the resistant organisms
(via food or direct contact)
•
Consequence assessment – considers the potential consequences of human exposure (take
account of importance of the antimicrobial substance for human medicine)
 Results in an overall qualitative risk estimation
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Authorisation of antimicrobials in the EU
Similar guidance on assessment of resistance potential is
published elsewhere
•
OIE (CVMP approach adapted from OIE approach):
Terrestrial Animal Health Code Chapters 6.10 (2011)
•
Codex alimentarius:
Guidance for risk analysis of foodborne antimicrobial resistance (CAC/GL 77-2011)
•
USA:
Evaluating the safety of antimicrobial new animal drugs with regard to their microbiological
effects on bacteria of human health concern – Guidance for industry #152 (2003)
Topics for discussion:
•
In your country, are any of the above used to guide the risk assessment of
antimicrobial resistance to public health?
•
If not, is other guidance used?
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Authorisation of antimicrobials in the EU
Ensure conditions of use are appropriate and advice to
veterinarians is clear
In addition to addressing the potential for resistance development and transfer we
need to ensure appropriate use of the product:
•
all use will select for antimicrobial resistance
•
avoiding unnecessary/inadequate use will prolong the time period for which the
substance remains active
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Authorisation of antimicrobials in the EU
Efficacy evaluation
CVMP guideline for the demonstration of efficacy for veterinary medicinal products
containing antimicrobial substances
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/02/WC500200984.pdf)
•
Indication should be justified:

use of antimicrobials for treatment of mild and transient infections that will resolve
spontaneously is questioned
–
preventative claims are not easily accepted, risk of infection should be very high
and consequence of infection severe
–
a metaphylaxis claim only accepted in conjunction with a treatment claim and never
as a separate indication
•
The microorganisms and strains against which the product is efficacious should be
demonstrated
•
the product information should list these bacteria for each target animal species and
indication for use
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Authorisation of antimicrobials in the EU
Efficacy evaluation
•
the product literature should advise that, whenever possible, laboratory diagnosis
and susceptibility testing should be carried out by the veterinary surgeon before
prescribing the drug
•
Determine the appropriate dosage regimen (dose, duration of treatment, route of
administration)
•
The appropriateness of instructions/advice provided in product information and
prudent use principles emphasised
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Authorisation of antimicrobials in the EU
Clear communication / Principles of prudent use
•
Clear communication with veterinarian is critical
•
In EU antimicrobials are prescription only medications
•
Indication including microorganisms and strains
•
Clear dosing regimen
•
Avoid deviations from approved dosing regimen (underdosing, insufficient treatment
duration, excessive treatment duration)
•
Criteria for determining whether appropriate to use product (1st line versus 2nd
line…)
•
Standard prudent use phrases to be included in product information, eg:
•
The <name of antimicrobial> should be used for treatment of severe infections only
•
The <name of antimicrobial> should be reserved for the treatment of clinical conditions
which have responded poorly, or are expected to respond poorly, to other classes
CVMP guideline on the SPC for veterinary medicinal products containing antimicrobial
substances
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/02/WC500070670.pdf)
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Authorisation of antimicrobials in the EU
Some specifics
• 3rd and 4th generation cephalosporins and fluouroquinolones should be reserved for
treatment of clinical conditions that have responded poorly, or are expected to
respond poorly, to more narrow spectrum antimicrobials
• Authorisation of 3rd and 4th generation cephalosporins and fluouroquinolones for
prophylactic use should always be limited to specific circumstances
• Use of cephalosporins in feed or drinking water for groups/flocks of animals is
strongly discouraged
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Authorisation of antimicrobials in the EU
Efficacy evaluation and prudent use
Topics for discussion:
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•
Are antimicrobial products evaluated for effectiveness against specific
microorganisms/strains?
•
Are the specific microorganisms/strains listed in the product information?
•
Is the dosing regimen established based on data?
•
Does use of antimicrobials require a prescription from a veterinarian?
•
Does product information recommend laboratory diagnosis/susceptibility testing?
•
Is prudent use advice routinely included in product information?
•
Do you follow particular guidance on prudent use?
Authorisation of antimicrobials in the EU
Antimicrobials as growth promoters
•
Subclinical exposure selects for resistance
•
Codex Alimentarius specifically advises that antibiotics should not be used in feed
for growth-promoting purposes in the absence of a public health safety
assessment, and that, in any case, their use should be minimized (Code of practice
to minimize and contain antimicrobial resistance CAC/RCP 61-2005).
•
In EU authorisation of antimicrobial feed additives was withdrawn in Jan 2006
Topics for discussion:
•
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is antimicrobial use allowed for growth promotion purposes in your country?
Authorisation of antimicrobials in the EU
Summary
•
Evaluate potential for antimicrobial resistance development (VICH GL27)
•
Assessment of risk to public health of antimicrobial resistance resulting from
proposed use (OIE/Codex Alimentarius/FDA/CVMP guidance)
•
Ensure conditions of use are appropriate (indications, dosing regimen…)
•
Ensure product information is clear and emphasises principles of prudent use
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Authorisation of antimicrobials in the EU
Topics for discussion
• Are MRLs (or equivalent) set locally or are standards set by external countries/bodies (eg Codex
Alimentarius) used?
• If MRLs (or equivalent) are set locally is impact on GI flora taken into account?
• Is VICH GL36 used?
• Is VICH GL27 used as a basis for considering the potential for development of resistance in the target
animal?
• In your country, are any of the above used to guide the risk assessment of antimicrobial resistance to
public health?
• If not, is other guidance used?
• Are antimicrobial products evaluated for effectiveness against specific microorganisms/strains?
• Are the specific microorganisms/strains listed in the product information?
• Is the dosing regimen established based on data?
• Does use of antimicrobials require a prescription from a veterinarian?
• Does product information recommend laboratory diagnosis/susceptibility testing?
• Is prudent use advice routinely included in product information?
• Do you follow particular guidance on prudent use?
• Is antimicrobial use allowed for growth promotion purposes in your country?
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Authorisation of antimicrobials in the EU