1 Environmental Exposure Units for Phase 3 Studies Ronald L. Rabin, MD Chief, Laboratory of Immunobiochemistry Center for Biologics Evaluation and Research USFDA

2 Demonstration of efficacy of allergen immunotherapy for seasonal allergens Well designed Double Blind Placebo Controlled studies Comparison to placebo and to a “baseline” year FDA accepts combined symptom and medication scores as the primary endpoint Studies must be adequately powered taking into consideration: -expected differences between treatment and placebo (small) -expected variability of each group (high)

3 Subjective nature of symptom scores Accepted differences between placebo and treatment groups Pivotal trials to prove efficacy of immunotherapy must be large; this requires multiple study sites. However: To induce symptoms, pollen levels at each site must be high, possibly for two consecutive years Studies of effective agents may fail due to poor pollen seasons Impediments to demonstrating efficacy of allergen immunotherapy for seasonal allergens

4 Grass and weed pollen profile in the Washington D.C. area, Kosisky SE, Marks, MS, and Nelson MR Ann Allergy, Asthma and Immunol 104:223; 2010

5 Tree pollen profile in the Washington D.C. area Kosisky SE, Marks, MS, and Nelson MR Ann Allergy, Asthma and Immunol 104:223; 2010

6 Biphasic annual grass pollen profile in the Washington D.C. area, Kosisky SE, Marks, MS, and Nelson MR Ann Allergy, Asthma and Immunol 104:223; 2010

7 Variation in Oak and Ragweed pollen counts in the Washington D.C. area, Kosisky SE, Marks, MS, and Nelson MR Ann Allergy, Asthma and Immunol 104:223; 2010

8 Pollen counts are highly variable within a single region The challenge of pollen variability increases with the number of study sites Variability in pollen seasons increases the variability of clinical symptoms enhancing the possibility of a failure to detect efficacy (type II error)

9 Environmental Exposure Units Contained rooms in which exposure to airborne substances is controlled Advantages studies are not limited to the period of natural pollination controlled and uniform allergen exposure no impact of weather conditions no impact of personal context (participation in outdoor activities, etc) ensured compliance timed symptom assessments

10 Examples of Environmental Exposure Units JH Day et al. Clin Exp Allergy Rev 6-31; 2006

11 Kingston, Ontario Environmental Exposure Unit JH Day et al. Clin Exp Allergy Rev 6-31; 2006

12 Consideration of EEU for clinical trials in support of licensure in the United States In March, 2009, a group of allergists met to explore the use of EEU for clinical trials to support licensure: Consensus EEU can provide uniform distribution of pollen Larger units require more monitoring Peak Nasal Inspiratory Flow may be an efficacy variable in addition to combined medication/symptom scores A priming phase must be included for seasonal allergens Mono-allergic subjects are unnecessary Natural exposure studies may also be necessary

13 Clinical trials in support of licensure in the US In February, 2010, the NIAID met with stakeholders to further discuss the use of EEU in Phase 3 studies Consensus Standards for EEU need to be set and harmonized Requires sharing of data (but not protected technology)

14 Clinical trials in support of licensure in the US An NIAID-hosted workshop with stakeholders in June, 2010 Attendees agreed to prepare a publishable document to discuss the need for EEU validation Consider preparing collaborative grant applications to fund EEU validation studies Study 1: Comparison of the Effectiveness of Common Seasonal Allergic Rhinitis Medications in the EEU and Under Natural Seasonal Allergen Exposure Study #2: Determining Inter-EEU Variability Under Standardized Allergen Exposure Conditions

15 Approach towards allergenics: Controlled vs. Natural Exposure Exposure ControlledNatural Food+- Hymenoptera+- Pets / Molds+/-+ Pollen?+ Allergen Type

16 Summary EEU are potentially an attractive tool for proving efficacy of novel products for allergen immunotherapy EEU studies alone may not be sufficient for demonstrating efficacy of immunotherapeutics; natural exposure studies may continue to be required Outstanding issues: Validation of even distribution of pollen throughout an EEU Harmonization of standards among the different facilities in North America and Europe Contribution of behavioral aspects of a group to bias of data

17 Acknowledgements/Announcement FDA Jay Slater Paul Richman DAIT/NIAID Alkis Togias Marshall Plaut Matthew Fenton

18 Variation in tree, grass, and weed total pollen counts in the Washington D.C. area, Kosisky SE, Marks, MS, and Nelson MR Ann Allergy, Asthma and Immunol 104:223; 2010

19 Biphasic annual elm pollen profile in the Washington D.C. area, Kosisky SE, Marks, MS, and Nelson MR Ann Allergy, Asthma and Immunol 104:223; 2010