Biomedical Engineering Reference
In-Depth Information
chosen to be appropriate to the type of study being conducted, and
phase III studies should include those patients that preliminary
studies suggest will be most likely to benefit from the new drug.
The size of the study population should be large enough to allow
for accurate statistical analysis; adequately powered to detect a
clinically meaningful difference between the treatment groups in
the primary outcome measure [
11
].
Control group
. The choice of control treatment should be chosen to
ensure both an adequate test of the safety and efficacy of the drug,
as well as to ensure the well-being of patients. The use of a placebo
is common, but may be impossible or inappropriate. In the case of
an intraocular implant, for example, there may not be a comparable
placebo, so either observation, a sham procedure, or an active
control must be used. An active control is chosen if there is signifi-
cant risk of disease progression if the patient is left untreated, and is
usually the standard-of-care for the indication under study (if a
widely accepted standard-of-care exists) [
11
].
Primary outcome measures and endpoints
. It is important that the
efficacy endpoints chosen are both readily quantifiable and clinically
relevant to patient health and quality of life. Well-validated surro-
gate endpoints can be used for health outcomes that take years to
manifest (such as blindness, paralysis, or death). Surrogate end-
points are not a direct measure of how a patient feels, functions,
or survives, but are considered likely to predict a long-term thera-
peutic benefit for the patient [
10
,
11
]. A commonly used surrogate
endpoint in ophthalmology, for example, is intraocular pressure
(IOP), which has been shown to correlate with the risk of eventual
loss of visual function in patients with glaucoma [
14
,
15
].
Outcome measures relevant to ophthalmology were recently
discussed at an international workshop convened by the EMA [
16
].
In the fall of 2011, approximately 200 experts in eye diseases from
Europe, Australia, Japan, and the US gathered to discuss the regu-
latory and scientific challenges in developing medicines for eye
disorders. Participants included representatives from the pharma-
ceutical industry, patient and physician groups, academia, and
European regulatory agencies. The regulatory viewpoint expressed
was that visual function endpoints are fundamental to the assess-
ment of ophthalmic products, but that measurements of anatomical
structure (e.g., changes in retinal or retinal vascular anatomy) can
also be valuable. Measurements of visual function can include visual
acuity, visual field, contrast sensitivity, and color vision, as well as
complex visual tasks such as reading, orientation, activities of daily
living, and even more complex concepts such as vision-related
quality of life (social skills, self confidence, coping skills). The
primary endpoint in clinical trials for retinal disease, however, is
usually some measurement of visual acuity, with an emphasis on
