Clinical trials of antibiotics are becoming more demanding, more
reliable... and (probably) less common
Placebo trials. Disease indications that do not heal spontaneously without antibiotics.
Field trials that have a closer resemblance to the conditions of use in the field. Second
choice antibiotics that are actually tested as second intention... The new guideline on
the efficacy of new antibiotics toughens the requirements, with the risk of discouraging
their development.
The European Medicines Agency (EMA) has published a draft of new guidelines on the
demonstration of efficacy of veterinary antibiotics.
The objective is clear. For antibiotics to be used less and better, they should also be assessed
better. However, there will probably also be less candidate substances submitted for
assessment.
The highlights of the future guideline include the following points.
Metaphylaxis and antibiotic prevention: against placebo
This is new: the guideline recognises the possibility to claim an efficacy for metaphylactic
use, but only in addition to a curative efficacy in diseased animals – because metaphylaxis is
defined as the treatment of apparently healthy animals that are in contact with diseased
animals (treated curatively).
Nor does the guideline exclude indications for prevention in case of high and severe
infectious risk. However, the trials demonstrating efficacy for metaphylactic or preventive
treatment will need to be compared to placebo treatment, and on good farms where antibiotics
are not used to mask poor hygiene. Such trials will be difficult to set up.
For oral treatment of animals in groups (oral powders and drinkable solutions), the
metaphylactic indication may be demonstrated on the basis of (tangible) results of the curative
treatment trial of groups including both healthy and diseased animals. That may be easier to
prove for oral substances than for injectables.
Placebo to assess spontaneous recovery
Until now, clinical trials have been comparative trials, mainly with older reference antibiotics.
The benefits compared to a spontaneous recovery (placebo) or non-antibiotic measures were
therefore not evaluated.
The new guideline recommends trials against placebo, even if the spontaneous recovery rate
is high, in particular in case of benign and transitory infections or multifactorial diseases. The
benefits of antibiotic therapy over other, non-antibiotic measures should be clearly
demonstrated.
Certain indications listed in the data sheet may no longer be acceptable in future.
Field trials closer connected to the field
Currently, field trials often lead to an overestimation of antibiotic efficacy compared to the
usual field conditions, due to the inclusion criteria and the exclusion of severe, recurring or
chronic cases (which are the most difficult to treat).
In future, the target animals should closer resemble those found in the field. Clinical trials
should be more realistic.
The objective is no longer limited to the demonstration of efficacy by selecting cases that are
likely to respond well to antibiotics, but also to better assess the recovery rates in the field.
A ‘good’ reference treatment
In comparative trials, the choice of the reference treatment is essential. The equivalence or
superiority of a new antibiotic will be easier to prove if compared to a moderately efficacious
antibiotic. The guideline demands that the efficacy of the reference antibiotic (at the approved
dose) is validated using recent sensitivity data. In other words, it will no longer be possible to
compare with a “poor” antibiotic, even if it is approved for the target indication.
2nd intention trials for 2nd intention antibiotics
Clinical trials should follow the official recommendations of antibiotic classification (1st or
2nd intention) in particular concerning critical antibiotics: third and fourth generation
cephalosporins and fluoroquinolones.
The clinical trials of these last-resort antibiotics should therefore be organised to include
(expected) therapeutic failure. However, to take into account the difficulty of organising such
trials in a large number of animals, the trials performed for second intention could be carried
out in a limited number of animals (without conclusive statistical results), in addition to a trial
demonstrating first-line efficacy (with conclusive statistical results).
A preference for plasma concentrations …
The pharmacokinetics/pharmacodynamics (PK/PD) approach, which consists of comparing
the in vivo concentration to the in vitro MIC, is well known. The new guidelines prefer this
approach in order to confirm a therapeutic dose or even to confirm an efficacy for rare
indications, including infections due to multiresistant bacteria.
The study is preferably carried out on the free fraction of the plasma concentration, as this
corresponds well to the levels in the biophase, where extracellular germs multiply. The
approach using tissue concentrations will need to be validated on forehand, which means it is
probably avoided. However, it seems to be accepted that this approach is not valid for all
antibiotics. Macrolides in particular have very low plasma concentrations, well below the
MIC.
Finally the MIC data must be recent (less than 5 years old).
“As short as possible”
The guideline encourages performing population pharmacokinetic studies on the basis of field
trials (among others for oral powders and oral solutions).
The duration of exposure to antibiotics, which cannot be determined by a PK/PD approach,
should be “as short as possible”. The objective is the avoidance of “unnecessary exposure to
antibiotics” and that of “unnecessary selection pressure of resistant bacteria”.
Clinical and bacteriological recovery
The efficacy should be assessed within a period to be justified, based on clinical, and if
possible, bacteriological criteria. This supposes sampling animals that appear healthy at the
end of the study. The clinical response is generally the first criterion of efficacy (with
exceptions).
In group treatment, e.g. in poultry, where individual assessment is not possible, the efficacy is
assessed for the group (e.g. evolution of the mortality rate) and based on post-mortem
examination with bacteriological analysis.
The guideline also demands a post-treatment follow-up to assess any possible relapses (due to
an insufficient efficacy) by separating them from relapses due to a re-infection (possibly by
another germ).
If possible, bacteriological test should be carried out in case of treatment failure and relapses.
Source:
European Medicines Agency (EMA). Second consultation of the guideline for the
demonstration of efficacy for veterinary medicinal products containing antimicrobial
substances.
Reference document EMA/CVMP/261180/2012.