Anne K. Ellis, MD MSc FRCPC FAAAAI
Testing a new treatment for allergic rhinitis can be an “iffy” process. The “Gold Standard” by which the US Food and Drug Administration (FDA) and other regulators look to determine proof of efficacy has traditionally been the in-season, outpatient clinical trial. These typically multi-center studies aim to capture the usual conditions under which the treatment is given. Allergic participants are exposed to sensitizing allergen(s) in their natural environment as part of their normal daily routine—pollens and so on—that are already giving them symptoms. As with any study or treatment, for that matter, studying people at home and work usually has its limitations. That is, people don’t take their medication as promised, weather is variable and affects things like pollen counts (even in peak pollen season!), and participants don’t do their “homework”, dutifully recording symptoms on schedule. [1]. Then there’s geography. Pollen levels can often be highly variable between sites and/or over the course of consecutive seasons, presenting logistical problems, and can significantly impact the evaluation of treatment[2]. Furthermore, each participant’s exposure level is not only influenced by local variables such as weather patterns, but also by lifestyle, including time spent out doors[3]. It’s no use testing for outdoor allergens when someone spends all his or her time indoors. What we really need is a way of controlling these environmental exposures.
Big-Name Antihistamines Stop Here On Way to Pharmacy
That’s where the Environmental Exposure Unit can help. Cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), budesonide (RhinocortAqua), mometasone (Nasonex)—these are just a few of the household names that have been tested in the EEU. Of course, there are many that have never become well known because they failed to show efficacy—not so long ago an oral-encapsulated immunotherapy compound bit the research dust. In the long run, I’m happy to say, EEU results are borne out by what I eventually see in clinical practice.
The EEU was developed to address the variables inherent in traditional studies, while still reproducing many of the conditions present outdoors[1;4;5]. The concept of the EEU is, in effect, ‘to bring the outdoors indoors’, under strictly controlled conditions to ensure equal allergen delivery to all participants. The EEU also provides 100 percent compliance with study medication and symptom-diary-card completion. Moreover, since all participants perform the same level of activity we don’t have to correct between those who spend their springtime on the softball field or gardening or those who lie on the couch reading or watching TV [4].
Drs. James Day and Reginald Clark (Departments of Medicine and Chemical Engineering, respectively, Queen’s University) developed the EEU (the first of this kind of facility in North America) in Kingston, Ontario, Canada. Initially, the facility was designed to investigate the respiratory effects of particulates and off-gasses from urea formaldehyde foam insulation (UFFI)[6;7]. These are considered to be culprits for that nasty modern problem multi-chemical sensitivity. In 1987, utilizing particulate technology that has been significantly refined over the ensuing years, the EEU was modified to focus on allergy research.
Fine-Tuning the Climate
The EEU is a unique, internationally recognized research facility that allows for as few as 5 to as many as 150 volunteers to be simultaneously exposed to ambient levels of airborne allergens such as ragweed pollen. Located within Kingston General Hospital, the EEU allows for the tight regulation of environmental variables such as air quality, temperature, humidity, CO and CO2 levels as well as the precise maintenance of allergen concentration[4]. The EEU uses 100-percent fresh air that passes through high efficiency filters, enters the EEU, and is then exhausted outdoors at a ventilation rate of 2500 cfm. Therefore, essentially, the volume of the room is replaced every 12 min. The temperature and humidity are maintained at 23°C ± 1°C and 40% relative humidity, respectively. Room conditions can be reproduced on different days and at any time of the year, something that cannot be achieved when you have to wait for spring, or any other season.
The pollen level within the EEU is highly regulated. Every 30 minutes seven Rotorod® samplers within the participant seating area are activated to ultimately provide information to the pollen dispersal equipment and ensure equal pollen distribution throughout the room. EEU allergen concentrations of 3500 +/- 500 grains/m3 have historically proven to produce allergic symptoms in the confines of the clinical trial timeframe; however, any target pollen concentration can be achieved.
Additional air samples are taken during each study to ensure that potential fungi or bacteria from the outdoors are not present and the HVAC filtration system is properly sealed. Each pollen batch is independently lab tested for fungi and bacterial contamination prior to dispersal within the EEU. To add to the stringent air quality standards in the EEU, even the cleaning products are specifically selected for low VOC release. The CO2 target is <850 ppm with ventilation rates that exceed the ASHRAE (American Society of Heating, Refrigerating and Air conditioning Engineers) standard for hospital treatment rooms. Any other particles in the room air are monitored using sticky surface sampling, and an accredited 3rd party laboratory conducts all outside testing.
The Participant Experience
The length of time people spend in the EEU depends on the study. Almost all studies begin with a “priming phase” where participants attend a minimum of 1 to 4 three-hour pollen exposure sessions to “re-awaken” their allergic reactivity. Once they reach the pre-determined qualifying symptom score (protocol dependent) they are sent home, then return on the study day. Depending on what we are testing, the study day can be anywhere from five hours to 14 hours long. For a typical antihistamine evaluation, they would return in the morning for two hours of pollen exposure. Those meeting the qualifying symptom score by 90 minutes are randomized and dosed at the two-hour mark, and then they record their symptoms every 20 to 30 min (protocol dependent) for the ensuing four hours of their visit. Often people return the next day to evaluate the duration of effect of the medication as well, and then a second dose is given. Evaluation of a nasal corticosteroid requires a longer exposure.
But enough about the science – what is it actually like for the participants in these types of studies? We try to make the experience of being in a room full of pollen as pleasant as it can be while still ensuring participants maintain their focus on why they are there – to carefully evaluate the anti-allergic medicine under investigation. Meanwhile, there’s food, wireless internet access, and participants often enjoy their usual seated activities such as reading, TV and knitting, and one fellow whose hobby is carving wax made us candles.
Safety is a high priority. Physicians stay in the room with participants and monitor them carefully. As we are located within the hospital itself, emergency care is literally steps away, if needed, but the EEU is fully stocked with all medications and equipment necessary to treat any unexpectedly severe allergic reactions.
In the FDA’s “Draft Guidance for Industry: Allergic Rhinitis: Clinical Development Programs for Drug Products” environmental exposure unit studies have been acknowledged as systems for evaluation of onset of action of anti-allergic medications for seasonal allergic rhinitis (SAR) as well as for the prophylactic treatment of SAR [9]. Both industry and regulatory agencies alike have expressed a desire to consider the EEU model as proof of clinical efficacy for IND submissions. To ensure this outcome is achieved, the author remains in discussions with the National Institute of Health, the FDA, and the Investigators from other EEU-similar facilities. For more information on the Environmental Exposure Unit, visit www.eeu.on.ca
References
1. Day JH, Ellis AK, Rafeiro E, Ratz JD, Briscoe MP. Experimental models for the evaluation of treatment of allergic rhinitis. Ann Allergy Asthma Immunol 2006; 96: 263-77.
2. Chervinsky P, Philip G, Malice MP et al. Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies. Ann Allergy Asthma Immunol 2004; 92: 367-73.
3. Akerlund A, Andersson M, Leflein J, Lildholdt T, Mygind N. Clinical trial design, nasal allergen challenge models, and considerations of relevance to pediatrics, nasal polyposis, and different classes of medication. J Allergy Clin Immunol 2005; 115: S460-S482.
4. Day JH, Briscoe MP. Environmental Exposure Unit: A system to test anti-allergic treatment. Ann Allergy Asthma Immunol 1999; 83: 83-9.
5. Day JH, Horak F, Briscoe MP et al. The role of allergen challenge chambers in the evaluation of anti-allergic medication: an international consensus paper. Clin Exp Allergy 2006; 6: 31-59.
6. Pross HF, Day JH, Clark RH, Lees RE. Immunologic studies of subjects with asthma exposed to formaldehyde and urea-formaldehyde foam insulation (UFFI) off products. J Allergy Clin Immunol 1987; 79: 797-810.
7. Day JH, Lees RE, Clark RH, Pattee PL. Respiratory response to formaldehyde and off-gas of urea formaldehyde foam insulation. Can.Med.Assoc.J 1984; 131: 1061-5.
8. Heffer MJ, Ratz JD, Miller JD, Day JH. Comparison of the Rotorod to other air samplers for the determination of Ambrosia artemisiifolia pollen concentrations conducted in the Environmental Exposure Unit. Aerobiologia 2005; 21: 233-9.
9. Guidance for Industry (Draft) – Allergic Rhinitis: Clinical Development Programs for Drug Products. April 2000. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER).
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Anne K. Ellis, MD MSc FRCPC FAAAAI. Assistant Professor and Chair, Division of Allergy & Immunology, Department of Medicine, Queen’s University. Email: ellisa@kgh.kari.net. Twitter: @DrAnneEllis