Clinical Trial Endpoints
To gain regulatory approval, Phase III trials need to evaluate accepted
clinical endpoints, which directly measures how a patient feels,
functions, or survives. Survival is not a pragmatically feasible
endpoint in the development of chronic CF drugs because these trials
would take years and only enroll patients with the most severe lung
disease. A surrogate endpoint is a laboratory measure or a physical sign
that can substitute for a clinically meaningful endpoint(24). Surrogate
endpoints may be used if they are strongly associated with direct
clinical endpoints and have been validated. Lung function is a surrogate
endpoint accepted by regulatory agencies based on the relationship
between lung function and mortality(25). However, how changes in lung
function are measured will influence study design. Most CF drugs have
been approved on the basis of an acute improvement in forced expiratory
volume in 1 second (FEV1), evaluated after weeks-months.
While an acute improvement in FEV1 may be beneficial to
people with CF, a more meaningful goal of chronic CF therapies would be
to slow the decline in lung function. This has been shown for a few CF
therapies,(26, 27) but these studies can take years to detect a
meaningful slowing of lung function decline. Longer studies may require
fewer patients, but such studies are also difficult to manage and can
become very costly. In the era of highly effective modulator therapy
(HEMT), the number of patients required in any study in CF may increase
significantly as health outcomes improve(28, 29).
Deciding between evaluating acute improvements in FEV1or slowing the chronic decline of lung function may depend on both the
intervention being studied and the patient population of interest.
Patients with mild disease may not be able to demonstrate acute
improvements in FEV1 (the so-called ceiling effect);
these patients may also experience the fastest decline in lung
function(30). Thus, drugs designed to address early lung disease or
prevent the development of more severe disease, such as
anti-inflammatory therapies, may opt for longer studies in healthier
patients. More recent studies have focused on acute improvements in
FEV1, and then been followed by prolonged open-label,
observational studies (see more details in Phase IV below), but
as overall lung function improves, demonstrating acute improvements in
FEV1 may become more difficult(29).
Reduction in the risk or rate of pulmonary exacerbations would seem to
be an attractive clinical endpoint to demonstrate efficacy of a new drug
because they directly affect how a patient feels, functions, and in
people with severe lung disease, survives(31, 32). However, pulmonary
exacerbations have proven problematic for several reasons(33). First,
there is no widely accepted and validated prospective definition.
Several definitions have been put forward and used in clinical
studies(6, 34, 35); the FDA has seemed to prefer a version of the Fuchs
criteria first used in the pivotal study of dornase alfa. Second, there
are several methods for determining changes in pulmonary exacerbations:
time to the first pulmonary exacerbation, frequency of pulmonary
exacerbation, total number of pulmonary exacerbations, etc. Time to the
first pulmonary exacerbation requires the smallest number of
participants, but may not be considered an acceptable outcome for
registration studies by regulatory agencies. Alternative measures of
pulmonary exacerbation require larger numbers of patients; this can be
mitigated by enriching a study population for patients who have a higher
risk of pulmonary exacerbations, but these patients may not be the ideal
population for the drug, and such a study could lack generalizability to
the wider CF population.
Patient reported outcomes (PROs) that directly measures a patient’s
health or their quality of life without interpretation by medical
professionals may be validated as surrogate endpoints(36). There are
several CF-related PRO tools (e.g., CFQ-R, CFRSD) (37, 38), and
improvement in symptoms using the CFQ-R was the endpoint for the study
that led to the FDA approval of inhaled aztreonam (Cayston ®)(39).
Growth has been used in the past as a validated surrogate endpoint,
though not in any recent drug trials(40). As CFTR modulator studies
expand to younger population, treatment associated effects on linear
growth is affected may become of interest(41).
The use of surrogate endpoints such as PROs may present difficulties
with study interpretation(24). Outside of CF, pivotal studies may be so
large that even small clinical differences may be statistically
significant. The difference may be less important in pediatric and/or
orphan disease studies, because these are typically smaller studies and
any statistically significant results are likely to also be clinically
meaningful. However, determining what difference is clinically
meaningful is important in many situations. An example would be a
non-inferiority study, which is designed to show that a new therapy is
not unacceptably worse than current standard therapy. This situation may
arise in CF when comparing a new drug within the same therapeutic class
(e.g., CFTR modulator or new inhaled antibiotic) to an established drug
when comparison with a placebo would not be acceptable(42). Clinician
surveys have indicated that many are uncomfortable withdrawing
efficacious medications(43).
Biomarkers may be used as surrogate endpoints and could potentially
speed up drug development. Biomarkers require validation to show they
reflect the biologic activity of a therapy as well as the relationship
with clinical outcomes(21). Biomarkers that have been explored in CF
include those that would reflect changes in CFTR activity (e.g., sweat
chloride, nasal potential difference, intestinal current measurement),
infection (e.g., bacterial density, detection of CF pathogens, and
inflammation (e.g., sputum neutrophil elastase activity, cell counts,
cytokines, and serum CRP). In order to validate biomarkers as useful
clinical surrogate endpoints, the relationships between biomarker
changes/clinically meaningful changes or thresholds and the likelihood
of subsequent clinical benefit must be clearly understood(24).
Otherwise, the use of biomarkers is limited because risks and benefits
cannot be fully assessed.
Recently, the FDA has demonstrated willingness to expand the use of
results from biomarker studies in the approval process for CFTR
modulators. Theratyping, the process of matching medications to specific
CFTR mutations based upon in vitro testing results, has been used
to expand the indication for ivacaftor beyond the original mutations for
which it was approved through the traditional regulatory approval
pathway(44). In 2017, after ivacaftor had been approved by the FDA for
people with at least one G551D mutation and deemed safe in people with
CF, ivacaftor was approved for people with CF with one of 23 other
residual function mutations based on how cells from people with CF
responded to ivacaftor in laboratory experiments(45). Similarly,
elexacaftor/tezacaftor/ivacaftor has been approved for all CFTR
mutations that can be demonstrated to respond in laboratory experiments
and has not been restricted to just those mutations present in clinical
trial participants.
Identifying appropriate clinical trial endpoints in young children may
be particularly difficult. Many endpoints that may be used in studies in
adults occur less frequently (e.g., deaths, pulmonary exacerbations),
have not been validated (e.g., age-appropriate PROs), or cannot be
measured readily (e.g., lung function in young children). Pivotal Phase
III studies have been pursued in older adolescents and adults in part to
avoid these limitations. Once drugs have been approved for use in older
children, the FDA has relied on safety data alone as the primary
endpoint in clinical trials in younger children with CF(46-48). This has
the added benefit of significantly reducing study size: pivotal trials
of ivacaftor included 100 patients 12 years and above, but only 38
children ages 2-5 years(48, 49). However, this strategy may not allow
for the detection of rare adverse events.