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Environmental Exposure Units for Phase 3 Studies

Ronald L. Rabin, MDChief, Laboratory of Immunobiochemistry

Center for Biologics Evaluation and ResearchUSFDA

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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)

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• 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

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Grass and weed pollen profile in the Washington D.C. area, 1998-2007

JANJAN FEB MAR APR MAY JUN JUL AUG SEP OCT1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

TreesGrass/Grass-like

Weeds

1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 JANJAN FEB MAR APR MAY JUN JUL AUG SEP OCT

Figure 1: Pollen Calendar for Major Tree, Grass and Weed Pollen in the Washington, DC AreaWeekly periods where >1% of the total annual pollen sum was observed (1998-2007)Weekly periods where >5% of the total annual pollen sum was observed (1998-2007)Weekly periods when annual "peak” daily averages were noted (1998-2007)"Peak Week"= Weekly period with the highest overall daily average (1998-2007)

Cockelbur

Queen Annes Lace

Pigweed/LQtrs

Ragweed

Sage

Cattail

Dock/Sorrel

Plantain

Nettle

Grasses

Sedges

Kosisky SE, Marks, MS, and Nelson MRAnn Allergy, Asthma and Immunol 104:223; 2010

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Tree pollen profile in the Washington D.C. area1998-2007

Kosisky SE, Marks, MS, and Nelson MRAnn Allergy, Asthma and Immunol 104:223; 2010

JANJAN FEB MAR APR MAY JUN JUL AUG SEP OCT1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

Trees

Hickory

Linden

Sycamore

Ash

Mulberry

Hemlock

Beech

Sweetgum

Walnut

Oak

Willow

Pine

Hackberry

Cottonwood

Alder

Birch

Cedar/Cyp/Jun

Maple

Elm

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Biphasic annual grass pollen profile in the Washington D.C. area, 1998-2007

Kosisky SE, Marks, MS, and Nelson MRAnn Allergy, Asthma and Immunol 104:223; 2010

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Variation in Oak and Ragweed pollen counts in the Washington D.C. area, 1998-2007

Kosisky SE, Marks, MS, and Nelson MRAnn Allergy, Asthma and Immunol 104:223; 2010

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• 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)

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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

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Examples of Environmental Exposure Units

JH Day et al. Clin Exp Allergy Rev 6-31; 2006

Vienna University Clinic

Kingston, Ontario

Vienna Allergy Center Copenhagen Atlanta Hannover

Size (m2) 13.78 303 21 5 360 47Capacity (# subjects) 14 160 24 1 150 18

ceiling to floorfiltered

outdoor airInlet vent

filteredoutdoor

airHEPA filtered

air

separate ceiling unit

pollen feeder into ventilation

unit

2nd air circuit

aerosol through

nebulizer into main unit

Typical allergen load 1500 grains/m33500

grains/m3

1400 grains/m3

50-100 ng/m3 Der p 1

3000-4500 grains/m3

1000-8000 grains/m3

Modified Burkard pollen traps

Rotorod samplers

Rotorod samplers

Laser partical counter/ Rotorod samplers

5 min 30 min 5 min 30 min 30 min

Ventilation/ dispersion system

Allergen load monitoring (method/frequency)

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Kingston, Ontario Environmental Exposure Unit

JH Day et al. Clin Exp Allergy Rev 6-31; 2006

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Consideration of EEU for clinical trials in support of licensure in the United States

In March, 2009, a group of allergists met to explore theuse 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

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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)

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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

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Approach towards allergenics: Controlled vs. Natural Exposure

Exposure

Controlled Natural

Food + -

Hymenoptera + -

Pets / Molds +/- +

Pollen ? +

Alle

rge

n T

yp

e

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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

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Acknowledgements/Announcement

FDAJay SlaterPaul Richman

DAIT/NIAIDAlkis TogiasMarshall PlautMatthew Fenton

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Variation in tree, grass, and weed total pollen counts in the Washington D.C. area, 1998-2007

Kosisky SE, Marks, MS, and Nelson MRAnn Allergy, Asthma and Immunol 104:223; 2010

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Biphasic annual elm pollen profile in the Washington D.C. area, 1998-2007

Kosisky SE, Marks, MS, and Nelson MRAnn Allergy, Asthma and Immunol 104:223; 2010