FDA Panel Considers Allergen Immunotherapy Development

Troy Brown, RN

January 22, 2016

The US Food and Drug Administration's (FDA) Allergenic Products Advisory Committee met Thursday to discuss issues related to the clinical development of food allergy immunotherapy products and aeroallergen immunotherapy products for the prevention of respiratory allergic disease. The committee was primarily concerned with allergen immunotherapy (AIT) in infants and children aged younger than 5 years.

"The importance of immunotherapy as a potential life-altering form of therapy for patients with food and aeroallergen hypersensitivity cannot be [overstated]," said Committee Chair Michael Nelson, MD, PhD, director, Medical Education Directorate, DHHQ, US Army, Office of the Surgeon General, Falls Church, Virginia. "They are two exceedingly common conditions with rising prevalence. The impact on quality of life and healthcare expenditures affects all age groups."

Food Allergy Immunotherapy Products

Food allergy is frequently diagnosed after assessment of patient history and immunoglobulin E antibody testing. Oral food challenge is usually conducted to rule out food allergy or confirm tolerance in patients with a history of allergic symptoms.

AIT for immunoglobulin E-mediated food allergy is an evolving area of clinical research. The goal of AIT is to desensitize food-allergic patients to prevent a catastrophic response after accidental exposure.

The types of AIT that are currently being studied are oral immunotherapy, sublingual immunotherapy, subcutaneous immunotherapy, and epicutaneous immunotherapy. Safety concerns vary according to the route of AIT.

Double-blind, placebo-controlled food challenge is repeated after AIT to evaluate the change in the eliciting dose (the lowest amount of the food that provokes objective signs and symptoms of allergy), if any, from baseline.

It can be difficult to establish a precise eliciting dose in children, especially in infants and toddlers, in part because some symptoms of allergic reactions in babies, such as drooling, vomiting, scratching, or drowsiness, can be missed or misinterpreted as normal.

Infants and very young children are unable to verbalize when they are having a reaction to oral food challenge. This limits the healthcare provider's ability to intervene as early as they would in older children and adults. For this reason, the committee believes infants and young children should be monitored more closely and for a longer period of time during food challenge.

It is not necessary to routinely establish intravenous access during oral food challenge, "but there should be criteria in place for when you would put in an [intravenous line]," said committee member John M. Kelso, MD, Division of Allergy, Asthma and Immunology, Scripps Clinic, San Diego, California.

The child's caregiver plays an important role during oral food challenge because they are already familiar with signs of allergic reactions in their child and can alert the healthcare provider to problems.

In AIT studies that use food challenge to demonstrate effectiveness, the main objective is to show a level of desensitization that translates to a clinically meaningful decrease in the risk for serious reaction to the allergen. In such studies, the primary endpoint is usually the level of desensitization in the treatment group compared with the placebo group.

Sustained unresponsiveness is the capacity to maintain desensitization to the allergen after treatment ends. Research has yet to define the length of time off therapy that would demonstrate clinically meaningful benefit; therefore, the clinical parameters that should demonstrate sustained unresponsiveness and appropriate research endpoints have not been established.

The panel discussed how much time off therapy is necessary to determine that a child demonstrates sustained unresponsiveness.

Prevention of Respiratory Allergic Diseases With AIT

The committee also discussed issues related to the clinical development of aeroallergen immunotherapy products for the prevention of asthma.

"Preliminary published evidence supports the concept that administration of AIT to individuals with allergic rhinoconjunctivitis can prevent the development of asthma," the FDA explained in an agency briefing. "[I]n a multicenter, prospective, randomized, open-label study of children with [allergic rhinoconjunctivitis] who were skin prick positive to grass and/or birch pollen, fewer children developed asthma after 3 years of treatment with AIT products compared to standard therapy alone (odds ratio 2.52; 95% CI: 1.3-5.1).”

Designing studies that demonstrate the effectiveness of AIT to prevent the development of asthma is difficult because the population being studied includes infants and children younger than 5 years who are at high risk for developing asthma but who have not yet developed asthma.

Diagnosis of Asthma in Infants Very Difficult

It's very difficult to define asthma in infants, several committee members observed. Wheezing in a child does not always mean they have asthma, but it can help identify children at risk for developing asthma later.

"[I]t is possible that you would exclude children [who have had wheezing during infancy] even knowing that a large percentage of them are not going to go and have what we would call established asthma," said Dr Kelso. "You have to decide whether to specifically include or specifically exclude such children to start with. Either way, it still complicates the issue. If you're seeing if you're preventing asthma, if a child wheezes with a cold when they're 3 [years old], does that mean your prevention didn't work, or was that a viral-induced wheezing episode that's going to be a relatively short-lived phenomenon in a child that's not going to go on to have asthma?"

"[In previous studies], if you [added] other signs of atopy, such as eczema and the presence of allergic rhinitis, the likelihood of persistent asthma went up quite a bit," said temporary voting committee member Richard Weber, MD, professor of medicine, University of Colorado Denver School of Medicine, National Jewish Health, Colorado.

Two or 3 years may not be enough time to identify children who develop asthma, said Michelle A. Joubert Gill, MD, PhD, assistant professor of pediatrics and immunology, divisions of infectious diseases and pulmonary vascular biology, University of Texas Southwestern Medical Center, Dallas. "The potential impact on asthma exacerbations…could be something that could be demonstrated in a shorter time period, but then you'd need to start with people who have defined asthma, and [they would] probably be older children," she added.

The route of AIT is an important consideration also, the committee members agreed. Sublingual AIT has fewer side effects and may be more easily tolerated by children than subcutaneous AIT.

The advisory committee members have disclosed no relevant financial relationships.

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