Biomedical Engineering Reference
In-Depth Information
5 Notes
IOP efficacy studies should be designed as ocular physiology
experiments and not assessments of toxicity or tolerability. It is
important to resist the temptation to add a large number of
ADME or tolerability/toxicity endpoints such as blood draws
(which can ruin acclimation to tonometry), fluorescein staining
and dilated pupil examinations (commonly included in many ocular
irritation scoring schemes), pupillometry, corneal sensitivity, cor-
neal pachymetry, noncontact specular microscopy, anterior seg-
ment optical coherence tomography, electroretinography, and
fundus imaging. Although some secondary endpoints do not affect
IOP measurements, many do and the addition of any secondary
endpoints must be done with the full knowledge of what impact
these have on the study achieving its primary objective of determin-
ing the ability of the test article to lower IOP. Additional considera-
tions in the design of an anti-glaucoma drug efficacy studies include
the following: (1) selecting the most appropriate species, (2) iden-
tifying the rate of nonresponders within the study population, (3)
determining whether normotensive or glaucomatous animals
should be used, and deciding (4) what secondary endpoints (if
any) to include, and (5) whether one eye or both should be dosed.
5.1 Efficacy Study
Design
Selecting the proper test species is one of the most critical aspects in
designing an anti-glaucoma drug efficacy study. It is essential to
correctly identify the species which possesses the putative target
receptors and the physiologic pathways necessary to elicit a
response. The considerable differences between species in terms
of cost, availability, and housing/handling requirements also are
important considerations in getting studies up and running as
quickly as possible in as cost-effective manner as possible. For
example, some species such as rabbits and dogs are easily housed
and cared for, readily available and rapidly acclimated to tonometry,
whereas this is less true for cats, pigs, and monkeys. The need for
sedation or general anesthesia in some species (such as monkey and
sometimes rats/mice) also can introduce confounding variables in a
complex and sometimes unpredictable fashion that may ultimately
call the validity of the study into question.
If one species is nonresponsive to a promising anti-glaucoma
drug it is important to determine if this is a species-specific finding
or if a similar lack of response would also translate to humans. There
are numerous examples of potent ocular hypotensive drugs in
humans that did not meaningfully alter IOP in one or more animal
species. This phenomenon is so common that it is very likely that
highly effective anti-glaucoma drugs in humans have been prema-
turely discarded, especially in the early screening stages of new
classes of drugs in which the receptor profiles and responsiveness
5.2 Species
Selection
