THE EEU SCIENTIFIC MODEL:

Common Questions & Answers

The EEU model has attracted significant attention from the scientific community and leaders in the field of allergy, and generated a number of common questions as one might anticipate with the development of a new methodology to study allergic rhinitis.

The concerns that have been raised during discussions about the EEU are critically reviewed along with evidence from studies undertaken to address these questions.

• Does the EEU represent ‘real life’ conditions experienced by participants?

  The original EEU concept was “to bring the outdoors to the indoors” so that the unwanted variables inherent in traditional seasonal allergic rhinitis studies could be controlled for or eliminated. Despite their ability to provide highly controlled efficacy, safety and pharmacological data, questions have been raised as to whether or not studies conducted in the EEU represent what is often referred to as ‘real life’ conditions. While allergic subjects participating in EEU studies are not exposed to the sensitizing allergen as in the natural outdoor environmental of traditional seasonal studies; in the EEU, controlled levels of the test-allergen are introduced into the air that the study participants are breathing, the most “natural” allergen delivery method when compared with other models used to study allergic rhinitis. In addition, while seated in the EEU study participants are free to engage in activities that are similar to those encountered in a “real life” setting at home such as watching movies, reading or talking with other study participants. Subjects may also briefly leave the seating area to stretch, obtain food and refreshments or use the washrooms.

  Subjects regularly report that the symptoms they experience in the EEU mimic those experienced outdoors during the pollen season. In an independent study undertaken by the Allergy Research Unit in Kingston, these observations were confirmed from the results of a survey in which subjects completed an assessment of their allergic symptoms during the ragweed season, and again while participating in a trial conducted in the EEU.

• What is the advantage of circulating only a single test-allergen in the EEU?
  Given that a number of allergens and environmental factors lead to the development of rhinitis symptoms in particpants, it may be argued that the single allergen exposure is not typical. However, the clinical manifestations of allergic rhinitis are identical with respect to single or multiple allergen exposure and the allergen involved. At the molecular level, allergic rhinitis is initiated by the interaction of allergen with the specific IgE. This is followed by the rapid release of histamine by mast cells and then by other cellular events which lead to the development of the full spectrum of allergic rhinitis symptoms (nasal congestion, sneezing, runny nose / post-nasal drip, nasal itching, eye itching, eye tearing, itchy palate / throat, cough). The results obtained on the efficacy of anti-allergic medications derived from EEU studies using one allergen are readily transferable for the treatment of allergic rhinitis caused by sensitivity to different allergens. Since a single allergen will do the job, there is no need to complicate the test conditions in the EEU by adding additional allergens. In fact, the exposure to multiple allergens has often been a concern in the “park” study setting.
• What is “priming”? Why “prime” study participants in the EEU?

  It has been shown that an allergic individual’s reactivity to a seasonal allergen increases within a season because of the “priming effect” of repeated allergen exposure. Priming by one allergen appearing early in the season can increase sensitivity to other allergens appearing later in the season. In the EEU, priming is undertaken whether the study is conducted in or out of season for the test-allergen in order to maintain consistency. In fact, this is considered one of the strengths of the EEU model because the priming component included in all EEU studies ensures that only subjects with adequate symptomatology required by a study protocol are admitted and randomized to receive double-blind medication.

  By incorporating priming in the EEU study design, it ensures that the predetermined level of reactivity to the test-allergen is developed in the priming phase and carries through to the study completion. Priming is an important element that should be considered in traditional and park studies as well. The rate and severity of symptoms developing during priming is a phenomenon that has been and continues to be studied in the EEU.

• What determines the allergen concentration used in an EEU study?
  Allergen concentrations in the EEU can be set at any level. For most studies in the EEU, to be consistent with peak outdoor levels reported by others and comparable with peak environmental levels found during the pollen season, the target ragweed pollen concentration has been 3500 +/- 500 grains/m3, a level that produces the full spectrum of allergic rhinitis symptoms in subjects exposed. Some subjects have modest symptoms to participate while others have more severe symptoms. It is important that all levels of symptoms are represented to accurately test the efficacy of the study medication.Daily environmental pollen levels are typically reported as a “24h average” leading to an underestimation of peak levels since pollen levels drop off significantly during the night. Another factor that can result in under reporting of pollen levels is the fact that the sampling environment used to collect the pollen is typically installed on building roof tops and pollen service lines are set at a height of approximately 15m in locations that are far from trees and other local pollen sources. However, it has been shown that pollen concentrations at 1.5m above the ground are much higher leading to the suggestion that the daily average count from a service line must be multiplied by a factor of 11-26 to compensate for these differences.
• Does the subject interaction in the EEU have any influence on study results? Can subjects distinguish efficacy and dose in the EEU?
  It has been suggested that subjects participating in EEU studies, like those in park studies, interact with other trial subjects and that these interactions may influence their experience or reporting of symptoms. Results obtained in the EEU have been shown to be reproducible and to discriminate between treatments and placebo, indicating that subjects record their symptoms accurately. This is supported by two EEU trials ( Day JH et al., J Allergy Clin Immunol. 1998; 101:638-645 and Day JH et al., Ann Allergy Asthma Immunol. 2001; 87:474-481), identical in design, which evaluated the comparative onset of action of two antihistamines. These two studies were the focus of a review publication (Day J, Clin Exp All Rev. 2003; 3:82-86 ) and critical to showing that EEU results can be reproduced when studies are conducted years apart and at different times of the year.

  Another concern raised about the EEU study setting in which subjects are gathered together in the same room is the potential for a greater placebo response because of the expectation of a beneficial effect from taking the study medication. In order to control for this possibility, all studies include a placebo control arm and subjects are made aware during the consent process, as well as other times over the duration of the study, that placebo or treatment is randomly assigned to each and every participant. Placebo response rates in the EEU have been found to be comparable with those observed in traditional rhinitis trials where subjects self-rate their symptoms using subjective severity scales (none, mild, moderate, severe), the symptom scoring instrument stated to be the preferred primary outcome measure by both the FDA and the EMEA.
  

• Are there any limitations on who can participate in EEU studies? Who makes up an EEU study population?
  EEU studies are open to all volunteers in the surrounding regions that meet the predetermined study eligibility criteria. As a policy, the EEU encourages all ethnic groups to participate in studies and has the benefit of being located on the campus of the internationally recognized Queen’s University and close to the Royal Military College and St. Lawrence College, allowing for the recruitment of an increased diversity of study volunteers.

  A further advantage of the EEU is that study participants can be transported and housed near the EEU facility, should it be required, to meet a specific study requirement.

• Are all EEU studies of short duration? Can longer studies be undertaken in the EEU?

  EEU studies have typically been designed to evaluate the onset and duration of effect of anti-allergic treatments. This information is essential to the efficacy of anti-allergic medications as determined by the ARIA/EAACI workshop group. Although most medications have been evaluated over 1-2 days in the EEU in order to assess onset of action and duration of effect of a single dose, a frequently requested end point, the EEU is readily adapted to studies lasting over extended time periods in order to assess steady state of treatments such as anti-histamines and nasal corticosteroids, or immunotherapy which may not provide results in months.

  Many evaluations may be undertaken during the course of a study in the EEU. While it is recognized that subjective self-rated symptom response to treatment is primary to the efficacy of a medication, the EEU is a setting where objective measurements of any outcome can be undertaken and have included Peak Nasal Inspiratory Flow (PNIF), rhinomanometry, acoustic rhinometry and pharmacokinetic sampling.

• Is there less experience with the EEU model than other methods?
  

  Overall, there is comparatively less experience with the EEU model than with traditional, seasonal allergic rhinitis trials. However, to date, as the leader in controlled allergen challenge research, a large number of studies have been conducted in the EEU and our contributions to the body of published literature on this model continues to grow and be evaluated by the scientific community. The EEU has been in operation for more than 20 years with over 25 studies published in peer reviewed journals, producing clinically relevant data that complements those from traditional and other trials. A CME review publication was written by those involved with the EEU to provide an important in-depth analysis on this subject.