Clinical Research

Clinical Research
Allergy Therapies:
Tables and Figures
Increasing the Probability of Clinical Development
Success
Introduction
The prevalence of allergic diseases is
increasing sharply in both developed
and developing countries. These diseases
include: asthma; rhinitis; anaphylaxis;
drug, food, and insect allergy; eczema;
and urticaria (hives) and angioedema.1
Allergic asthma and rhino-conjunctivitis
are the most common. Asthma incidence
is rising, affecting some 300 million
people worldwide.2 Allergic rhinitis
(AR) affects an estimated 10-30% of the
world’s population, with prevalence rates
also increasing worldwide.1
Management of allergic diseases
is based on trying to eliminate the
trigger (there may be one or several)
or to induce tolerance. Allergen-specific
immunotherapy induces tolerance by
redirecting the immune response away
from the allergic pattern. Management
of these patients also requires drug
treatments focused on blockade of
key mediators of inflammation. Antiinflammatory agents, which block the
activation of key cytokines that augment
and sustain airways inflammation, are
also used. In addition, more targeted
therapies are useful in selected patients.3
This
paper
discusses
possible
approaches to improving the probability
of success for allergy and respiratory
drug development programmes. To assist
readers who are interested in this topic
but may not be familiar with some of the
nomenclature employed, Table 1 presents
a list of abbreviations.
Current Status of Clinical Trials in Allergy
As understanding of allergic diseases
has increased, the number of potential
therapies in development has risen
in parallel. As shown in Table 2, there
are currently around 120 compounds
being developed for asthma and 60 for
rhinitis. The figures presented in Table 3
demonstrate that the number of clinical
trials for potential allergy therapies has
been rising sharply in recent years,
growing from approximately 100 in
2009 to almost 400 in 2013.
We carried out a search in June 2014
to determine the main geographic areas
of activity: the results are presented
48 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Table 1: List of Abbreviations
AHR
AIT
AR
ATS
CSMS
EAACI
ERS
ESPIA
HRQL
IgE
PAR
PER
PBI
PIF
QoL
RQLQ
RR
SAR
SF
SPT
TNSS
VAS
Airway hyperresponsiveness
Allergen immunotherapy
Allergic rhinitis
American Thoracic Society
Combined total symptom score and medication score
European Academy of Allergy and Clinical Immunology
European Respiratory Society
Satisfaction Scale for Patients Receiving Allergen Immunotherapy
Health-related quality of life
Immunoglobulin E
Perennial allergic rhinitis
Persistent allergic rhinitis
Patient Benefit Index
Peak inspiratory flow
Quality of life
Rhinoconjunctivitis Quality of Life Questionnaire
Recruitment rate
Seasonal allergic rhinitis
Short-form health survey
Skin prick test
Total nasal symptom score
Visual analog scale
Figure 1: Distribution of Allergy Trials in 2013
Figure 1: Distribution of Allergy Trials in 2013
Table 2: Number of allergy compounds in development
Number of compounds in development
Phase 1
Phase 2
Phase 3
Asthma
37
61
24
Rhinitis
8
35
19
Table 2: Number of allergy compounds in development
Table 3: Number of new allergy studies per year, 2009-2013
Number of new allergy studies per
year
Summer 2015 Volume 7 Issue 2
Clinical Research
Table 3: Number of new allergy studies per year, 2009-2013
Number of new allergy studies per
year
2009
98
2010
138
2011
142
on
investigational
drugs from the top
50 firms in terms
of pharmaceutical
sales, including 812
compounds, which
had 1369 failed
indications; reasons
were established for
failure by clinical
phase for 410 of
these
compounds
and 659 indications.
Key
findings
included:
•
In Phase I,
commercial reasons
2012
253
were
the
most
common cause of
failure, accounting
for 40.9% of all
2013
387
failures.
Efficacy
and safety issues
were approximately
equally
frequent,
each
accounting
Table 3: Number of new allergy studies per year, 2009-2013 for slightly less than
30% of those failures.
graphically in Figure 1.4 Although the
•
Efficacy
main areas of activity are the United
issues outnumbered commercial
States (191 trials in 2013) and Europe
considerations by 2 to 1 as the
(115 trials in 2013), there is activity in
leading reason for Phase II failure.
all major regions and both hemispheres.
This finding is consistent with the
This is the result of new strategies to
intent of Phase II studies, which is to
advance studies by finding more trial
obtain data on the effectiveness of
participants and/or investigate exposure
the drug for a particular indication
to specific allergens.
or indications in patients with
the disease or condition. Efficacy
A recent review by Citeline5 showed
and commercial issues were
that despite differences in sponsorship
more prevalent than safety issues
across therapeutic areas, the relative
as reasons for Phase II failure,
utilisation of the top 20 countries is
accounting for 53.9%, 27.3% and
generally consistent across therapeutic
17.2% of failures, respectively.
areas, with the United States remaining • In Phase III, 52% of failures were
the most-utilised country. It also is
due to lack of expected efficacy;
noteworthy that these top 20 countries
safety issues accounted for nearly
include
Eastern
European,
Latin
twice as many Phase III failures as
American, and Asia Pacific regions. It
did commercial reasons, at 30% vs.
is clear that Eastern Europe has become
16%.
an important region and that growth in
utilisation of countries in Latin American More than half of development
and Asia Pacific regions is likely in the discontinuations (54.3%) in respiratory
future. In this competitive environment, trials globally were related to efficacy
a high level of planning with accurate concerns.
study design, strategic study setup, and
high quality data capture is needed to
An earlier Tufts study published in
complete successful allergy studies.
Nature7 identified a clinical approval
success rate of 4.8% for respiratory
In 2013, the Tufts Center for the Study of products
originating
within
the
Drug Development published a summary pharmaceutical industry that were first
of clinical development failures for the tested in humans between 1993 and
period 2000-09.6 The study was based 2004.
www.ipimedia.com
Another study1 of clinical development
success rates found the highest likelihood
of approval from Phase I at 18.2%
(n=720) in drugs for indications grouped
together as “other”, which included
allergy, gastroenterology, ophthalmology,
dermatology,
obstetrics-gynaecology,
and urology.8
Improving Probability of Success
Possible approaches to improve the
probability of success for allergy
and respiratory drug development
programmes and their clinical trials
centre around issues in study design,
setup, and delivery:
Study Design
• Selection of primary outcomes
should be based on current
regulatory guidance, but there are
discrepancies between regulatory
guidance
and
science/clinical
practice; in addition, there are
regional regulatory differences. For
example, although common dossiers
are used, the United States Food
and Drug Administration (FDA) and
European Medicines Agency (EMA)
have granted different summaries
of product characteristics for some
compounds, and one agency may
ask for additional data despite the
product having been approved by
the other.
• Patients’
phenotypes
are
important. Improved knowledge
of disease pathophysiology has
enabled identification of various
inflammatory
pathways
and
mediators. New compounds are
now being developed addressing
specific mediators. These require
studies designed for the specific
populations where each mediator
plays a key role.
Study Setup Strategy
• Country selection is key, because
for a new study the choice may
contribute to several issues. For
example,
regulatory
approval
timelines may differ significantly by
region, and even within regions they
may not be fully harmonised, despite
recent attempts under the new
European Voluntary Harmonization
Procedure.9 Recruitment rates may
also depend on the structure of
health services, and on local rules
and practices.
• Recruitment rate (RR) predictions
need to be realistic. Overestimation
INTERNATIONAL PHARMACEUTICAL INDUSTRY 49
Clinical Research
•
•
•
of RR is a common issue in clinical
trials. Estimates based on investigator
interviews may be overly optimistic.
Various factors play a role here,
including interest from patients and
investigators in participating (does
the potential therapy address an
unmet need?), the burden of the
study for study participants and/
or investigator sites, and the safety
of participants (is standard of care
allowed, or is there a placebo arm?).
Competition is intense for both
participants and site resources.
Operational strategy should be
based on proactive risk-mitigation to
help avoid issues such as recruitment
delays. The main factors that may
play a role in patient recruitment or
compliance should be identified and
remediation strategies should be
ready to implement if needed.
Protocol amendments result in
study delays while they are being
approved. Therefore, adequate
multifunctional review of the protocol
and the case report form is essential
before regulatory submission takes
place.
Study Delivery
• Study compliance may be an issue
in long-term studies, especially those
designed to be carried out over threeto-five years’ duration, including
periods of treatment. Special
consideration should be given to
studies that include paediatric or
adolescent patients.
• Recruitment challenges may include
patients being required to undergo
selection procedures out of season
or within season, and/or excluding
other
concomitant
allergens,
depending on protocol definition.
A good database of patients and
pollen count availability in the area
are key elements in pre-selecting
participants and opening recruitment
when pollen reaches a minimum
level, for example. Some studies
may benefit from support tools such
as advertising: such tools should
be selected with care for optimum
effectiveness. Any patient-related
documents must be approved by the
ethics committee.
• Screen failure and/or drop-out
rate -- contingency plans, including
alternative sites or countries,
should be in place for higher-thananticipated rates.
• Data issues – such as poor data
50 INTERNATIONAL PHARMACEUTICAL INDUSTRY
quality, lack of homogeneity in
spirometry, or missing data – may
result from the fact that most allergy
clinical trials are designed and
statistically powered using subjective
measurements (symptom scores).
In such cases, inter-participant
variability tends to be wide, creating
a need for large sample sizes,
placing more individuals under
evaluation, and increasing costs and
timelines. Efforts to improve data
quality are one of the most important
elements in these studies. Investigator
selection should be based on a
history of proper management
of diagnostic tools and previous
experience in grading results and
patient symptoms.
exposure units, and allergen chambers.
The features of each are considered in
turn.
Early
Studies:
Pharmacodynamic
Models in Allergy
Pharmacological approaches used to
identify allergen sensitivities include
challenge tests and a variety of models,
such as skin prick tests, nasal provocation,
ocular,
bronchial,
environmental
Skin prick tests are the subject of
a European Academy of Allergy and
Clinical Immunology (EAACI) position
paper,12 representing a validated method
that has been used as a surrogate marker
in several clinical trials. In addition,
recent data on skin tests support that
Skin Tests
Skin prick tests represent a low-cost,
rapid, and accurate method of identifying
allergen sensitivity. These are used to
confirm sensitisation in immunoglobulin
E (IgE)-mediated allergic disease in
subjects with rhinoconjunctivitis, asthma,
urticaria, atopic eczema and food and
drug allergy.10 Such tests are often used
in advance of nasal allergen provocation
tests, due to the correlation between the
dermal and upper respiratory effects of
antihistamines.11 There is a long-standing
tradition of extrapolating data from the
skin to the airways in clinical practice.
Figure 2: EAACI recommendations for scores in allergy clinical trials
EAACI recommendation for scores in allergy clinical trials
Nasal
Daily
Symptom
Score
(dSS)
Ocular
(in pollen
allergic pat)
Daily
medication
score
(dMS)
Combined
symptom
and
medication
score
0 = no symptoms
Itchy, sneezing,
running and
blockade nose
1 = mild symptoms
(sign/symptom clearly
present, but minimal
2 = moderate symptoms
(definite awareness of
sign/symptom that is
bothersome but tolerable)
0-3
Watery, red eyes
3 = severe symptoms
(sign/symptom that is
hard to tolerate; causes
interference with activities
of daily living and/or
sleeping)
Oral and or topical non-sedating anti
H1
1
Intranasal cortis (+/-) antiH1
2
Oral corticosteroids (+/- antiH1 +/nasal cortis)
3
dSS + dMS
awareness; easily
tolerated)
0-6
(CSMS)
Summer 2015 Volume 7 Issue 2
Clinical Research
suppression of the late skin response
may be necessary, but not sufficient,
for the therapeutic effect of allergen
immunotherapy (AIT).
Nasal Provocation Tests
In nasal provocation tests, the allergen
may be applied in powdered form, via
sprays or nebulisers, from a syringe,
topically using cotton wool, or by
impregnation onto paper discs. An
advantage of this test is the potential
for critical evaluation of the kinetic
response to stimuli, rechallenge and
treatment. Response can be assessed
both subjectively and objectively by a
variety of methods: using baseline and
study total nasal symptom score (TNSS);
obstruction can be measured objectively
using nasal peak inspiratory flow (PIF)
or rhinomanometry; and rhinorrhoea
can be quantified by measuring weight
of tissues with nasal secretions. However,
nasal PIF and rhinomanometry are
not thoroughly standardised and have
not been validated. Nasal provocation
tests are the subject of an EAACI
position paper,14 which notes that nasal
provocation tests are useful in proof-ofconcept and dose-ranging studies, and to
evaluate the mechanism of inflammation.
Conjunctival Provocation Test
In the conjunctival provocation test, the
allergen concentration applied is usually
higher than environmental levels, a
factor that must be taken into account
when determining clinical relevance.
The EAACI position paper on this type
of test notes that it is a validated method
that documents conjunctival response
to AIT, yielding similar results to nasal
provocation testing and bronchial
challenge. The conjunctival provocation
test
comprises
mostly
subjective
parameters (using a scoring system
for symptoms), but does not include
parameters that can easily be measured
objectively. Moreover, at present, there is
heterogeneity in the scoring system for
this type of test.
Environmental Exposure Chamber
The EMA requires justification for the
use and validity of an environmental
exposure chamber, and both the FDA
and EMA restrict this to a limited role and
provide no guidance on how to assess
results.
The use of an environmental exposure
chamber is recommended in seasonal
allergic rhinitis (SAR) prophylaxis trials.
Useful properties include the ability to
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perform spirometry, pharmacokinetics,
rhinometry, electrocardiograms, nasal
PIF, tonometry, slit lamp exams, analysis
of inflammatory biomarkers and skin
prick testing.
The EAACI position paper on this topic14
notes that several studies have shown
the onset of AIT effects,25 and that there
is good correlation between symptom
responses of given patients to natural
exposure and within the chamber.
Relatively few environmental exposure
chambers exist internationally, and the
reproducibility of results among and
within sites has not yet been determined.
Pending results, an environmental
exposure chamber is likely to be a good
option as an adjunct to natural exposure
studies for Phase III randomised clinical
trials (RCTs).
Bronchial Challenge
The bronchial challenge is a wellcharacterised and useful tool for
understanding the mechanisms of
allergic airway inflammation and
airway hyper-responsiveness (AHR).
Epidemiologic
studies
demonstrate
that environmental allergens are an
important and increasing cause of
asthma, resulting in bronchoconstriction,
airway inflammation, and direct AHR.
The bronchial challenge was used as
the rationale for developing many of
the animal and subsequent human
models that have been used to study the
immunology of allergic asthma and the
efficacy of new therapies. The allergen
challenge in allergic asthma is the only
model of inflammation that accurately
reflects the syndrome of asthma in a
controlled clinical research environment.
Allergen Provocation Tests
For allergen provocation tests, the
EAACI
recommendations
highlight
the opportunity for more standardised
procedures, the ability to control
the environment (e.g., temperature,
humidity), an avoidance of seasonal
variation and the performance of
single-centre studies requiring fewer
participants.26 At present, there is no
substitute for the clinical response to
natural allergen exposure as the primary
outcome in Phase III trials. Allergen
provocation tests are recommended for
understanding underlying mechanisms,
biomarker discovery, proof-of-concept
for onset of action, novel immunotherapy
approaches, and allergen dose ranging.
Efficacy Clinical Trials in Allergic Rhinitis
Study Designs: Regulatory Guidance &
EAACI Position Paper
The FDA13 and EMA14 have both issued
guidance on the clinical development
of medications for the treatment of AR,
recognising multiple issues involved in
conducting meaningful trials in this area.
These include multiple allergenicities and
comorbidities, subjective measures, the
fact that subjects may be asymptomatic
at recruitment, inter- and intra-subject
variability, differences in pollen exposure,
and the existence of multiple endpoints.
A
recently-published
EAACI
position paper on standardisation
of clinical outcomes in allergen
immunotherapy clinical trials outlines
recommendations for nine domains of
clinical outcome measures.15 As the
primary outcome for future RCTs in AIT
for allergic rhinoconjunctivitis, the paper
recommends a homogeneous combined
total symptom and medication score
(CSMS) as “a simple and standardized
method that balances both symptoms
and the need for antiallergic medication
in an equally weighted manner.”
The FDA and EMA recommend at
least two adequate and well-controlled
efficacy trials for approval of a rhinitis
indication. According to regulatory
guidance for these trials, the doseresponse should be evaluated using either
clinical or validated pharmacodynamic
studies. The protocol should involve
randomisation, placebo and active
control arms, including double-blind,
parallel-group designs, ideally with a
placebo run-in period. Non-inferiority
trials are not possible because of lack of
sensitivity, and superiority trials should
be conducted against a well-established
comparator with the same route of
administration. Non-inferiority cannot
be claimed from superiority trials in the
absence of a placebo arm for internal
validation.
Regulatory guidance specifies that
pollen counts should be measured at
the different study centres. For SAR,
randomisation of participants at each
centre should be conducted over a short
period to reduce variability in allergen
exposure. For perennial allergic rhinitis
(PAR), randomisation should take place
outside the pollen season. According
to the FDA, the study duration should
be two weeks for SAR and four weeks
for PAR. Under EMA guidelines, study
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Figure 3: Factors influencing strategy for allergy clinical trials
•
•
duration may vary depending on the
onset of action of the product, indication
sought (treatment vs. prevention), and
duration of allergen exposure expected:
in general, the study duration should be
2–4 weeks for SAR, and 6–12 weeks for
PAR.
From
a
regulatory
perspective,
acceptable approaches to symptom
evaluation include:
• Subjective symptom scores on a
diary card, using a scale from
zero (absent) to three (severe), with
recording of symptoms such as
obstruction, sneezing, rhinorrhea,
nasal itching and ocular itching.
A visual analog scale (VAS) may
also be used for persistent allergic
rhinitis (PER); this is a psychometric
response scale to assess global
rhinoconjunctivitis discomfort. The
VAS can also assess every symptom
and its effect, with patients rating
symptoms by placing a vertical line
on a 10cm line representing severity
from zero (no symptoms) to 10
(‘highest level of symptoms’).16
• CSMS, which is recommended by
both the FDA13 and EMA.14 As the
use of rescue medication has an
effect on symptom severity, the EMA
guidance notes that “therefore, the
primary endpoint has to reflect both,
symptom severity as well as the
intake of rescue medication.”14
• The Rhinoconjunctivitis Quality of
Life Questionnaire (RQLQ),17 an
interviewer- and self-administered
instrument that measures the
functional impairments that are
most significant to adult patients
due to their seasonal or perennial
rhinoconjunctivitis of allergic or nonallergic origin.18 The RQLQ has a
seven-point scale, with higher scores
reflecting lower quality of life. This
approach has been validated and
appears to be responsive to change;
it is useful for measuring changes in
health-related quality of life within
a group, but not among groups.
However, completing the RQLQ
is a lengthy process, and might
be cumbersome for clinical trial
52 INTERNATIONAL PHARMACEUTICAL INDUSTRY
participants if required repeatedly.
In this case, use of a ‘mini-RQLQ’
may help reduce the burden.
Days free of symptoms.
Days free of medications.
Regulators will accept protocols that
involve more than one primary endpoint
(co-primary endpoints) if these are
ranked and predefined for pan-European
authorisation, but, in this scenario,
outcomes for all endpoints need to be
positive.
The EAACI’s 2014 position paper15
includes recommendations for scores in
allergy clinical trials as shown in Figure
2. The paper recommends the CSMS as
the primary endpoint for allergen
immunotherapy clinical trials for allergic
rhinoconjunctivitis. Also included are
recommendations on health-related
quality of life (HRQL). For the EMA, an
HRQL assessment can be included as a
primary endpoint when improvement in
quality of life is planned as a label claim,
or as a secondary one. There are two
main types: generic (SF36, SF12) and
specific (RQLQ, as discussed previously).
Other elements examined by the position
paper include:
•
•
•
•
VAS: global assessment/individual
symptoms, and secondary outcomes.
“Well days” vs. “bad/severe days:”
EMA recommends evaluation of
‘days with symptom control’ as ‘days
without intake of rescue medication
and a symptom score below a
predefined and clinically justified
threshold’; and “symptom-free days”
as secondary endpoints. In clinical
trials, ‘severe’ is defined in each day
where a three is recorded for any
symptom.
Global assessments and patient
satisfaction, including the Satisfaction
Scale for Patients Receiving Allergen
Immunotherapy
(ESPIA),19
and
Patient Benefit Index (PBI).20
Rhinitis control assessment tests, such
as CARAT10,21 RCAT,22 and RAPP;23
these are quick, easy, validated, and
available in multiple languages.
Recruitment in Allergy Trials
With this dual approach – regulatory
and updated science-oriented common
study design – features in allergic rhinitis
trials include: the use of a placebo
control; entry criteria designed to identify
diagnosed patients with at least two
pollen seasons or two years’ history of
specific allergy; and with most studies
allowing inclusion of mild asthmatics
(controlled with minimal exacerbations,
and potentially including periodic
spirometry for studies that include
asthmatic
evaluation).
Adolescents
are often included in 'adult' studies.
For inclusion, participants must have
demonstrated sensitivity to a specific
allergen based on the skin prick test and/
or IgE, and are required to complete
daily symptom scores and periodic
quality of life (QoL) questionnaires. They
must have qualifying allergy symptom
scores at screening and during the runin period, plus a positive skin prick test
(the longest diameter of flare ≥ 10 mm
and wheal diameter ≥ 5 mm, greater
than the negative control). Subjects
must be positive for specific IgE against
study allergen (at least IgE Class 2) at
the screening visit. Subjects may be
excluded if they have clinically significant
confounding symptoms of allergy to
other allergens potentially overlapping
the allergen-related season (for example,
tree, grass and ragweed allergens, dust
mites and moulds). The protocol may
include serial blood sampling for PK,
IgE, and repeat skin prick tests (SPT) and
may exclude previous immunotherapy
treatment in allergen-specific trials.
There is usually a highly specific list of
prohibited medications.
Screen Failure
The major reason for screen failure
among potential allergic rhinitis clinical
trial participants is the required SPT
reaction and/or IgE level. Other factors
include confounding allergies; prohibited
medication use; lack of a documented
two-year history of allergy; the need
for clinical study site personnel to be
trained to carry out and read SPTs, and
to pre-identify qualified individuals;
participants’ diary compliance/diary
fatigue; and issues with including
paediatric patients due to the requirement
for SPTs and blood sampling.
Screen failure rates can be reduced
in several ways. For example, one
is to develop a phone pre-screening
questionnaire, and another is for clinical
project managers to contact the sites with
highest screening failure rates to offer
education on pre-screening steps. Screen
failure information can be included in
site newsletters with suggested corrective
measures,
and
clinical
research
associates can reinforce these messages
Summer 2015 Volume 7 Issue 2
Clinical Research
when interacting with sites. It can also be
helpful to set up a webex site for training/
retraining of the principal investigator
as needed, with continuous review and
potential closure of screening at sites with
high failure rates that do not improve
after training.
Recruitment of Patients
In general, many factors influence
recruitment rates for allergy clinical trials,
such as study duration, treatment options,
study interest and competition, patient
access to physicians and healthcare
providers, site capability, standard of
care and physician access to patients
(see Figure 3).
Data Collection
Potential issues related to data collection
during allergic rhinitis trials include:
•
•
•
The study outcomes depend on
reporting by clinical trial participants.
The rating of symptoms is subjective,
and participants may not use scoring
ranks appropriately.
Paper diaries pose data collection
hurdles, including: inability to track
•
compliance in real time; the fact that
if the participant has ‘diary fatigue’,
data can be lost over long periods;
if a paper diary is lost, then all
data are also lost; data are entered
manually; there may be participant
identifier
errors;
and
diary
completion may be inconsistent.
Many of the issues related to paper
diaries can be addressed using
e-diaries, which provide one place
for the trial participant to collect all
required information, prevent data
fabrication and late entry, and can
be monitored closely for participant
compliance.
Despite being commonly performed
in clinical practice, spirometry
can be challenging in the research
environment, as the results obtained
require cooperation between the
participant and the technician
and are dependent on technical
and personal factors. Calibration,
reference
equations,
use
of
different types of equipment, and
interpretation of flow-volume loops
generally differs in clinical practice
compared with research, thereby
resulting in variability. Attempts to
standardise spirometry have included
several
publications
including
“Standardization of Spirometry”
and subsequent American Thoracic
Society/European
Respiratory
Society
(ATS/ERS)
updates.24
Centralised spirometry includes sites
receiving the same equipment (e.g.,
spirometer and calibration syringe)
loaded with study-specific software.
Sites are trained in the proper use of
the equipment and all data are sent
to a central server database where
the results are quality controlled by
an external over-reader. The overreader analyses the spirometry
results and reviews whether the
proper volume flow loops have
been selected according to ATS/
ERS guidelines, and are acceptable
and reproducible. Feedback from
the over-reader to the sites helps
to correct errors and improve
performance, thereby decreasing
variability across the study.
In summary, centralised spirometry
reduces errors and discrepancies in data
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and helps to ensure the quality of the
data for these key parameters.
Concluding Comments
In developing the right approach
to clinical trials for potential allergy
therapies, key points include the need
for proper study design, appropriate
participant selection, and high data
quality. For proper study design, an
integrated protocol should be developed
to demonstrate proof-of-concept in the
target patient group. Predisposing factors
in the patient population should be taken
into account, along with seasonal timing,
variability in response, and potential
for multiple exposures to allergens.
Study design should specify the route
of allergen administration – airway,
dermal, nasal or ocular – and identify
potential pharmacodynamic outputs and
appropriate biomarkers.
For appropriate participant selection,
clinical trial sites with allergy experience
should be selected, and backup sites
should be identified as a contingency.
Split SPT and IgE testing should take place
prior to all other screening procedures,
helping to reduce costs, and using
commercial-strength SPT antigen coupled
with an interactive voice response system
to ensure classification of the shortform health survey (SF) is performed in
a timely manner. Each site should use a
detailed pre-screening questionnaire.
For optimum quality, a retention plan
should be implemented to minimise
dropout rates, with a programme of
disease education and clinical team
training. An eDiary incorporating
reminders and tools to maximise subject
compliance should be used, along
with best practices in monitoring and
standardisation.
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Dr Juan Gispert is
Senior Medical Director
and Head of Quintiles’
Allergy and Respiratory
Center of Excellence.
He received his M.D.
from the University of
Navarra, followed by
a Ph.D. in Public Health, Statistics and
Epidemiology from the University of
Zaragoza, and post-graduate degrees in
Pharmaceutical Medicine and in Design
and Statistics in Health Sciences, both
from Barcelona University, Spain. He
is experienced in all aspects of clinical
trials, from development and design to
regulatory submissions and medical
affairs.
Email: [email protected]
Summer 2015 Volume 7 Issue 2