The FDA has issued new guidance for clinical trials testing drugs designed to treat hay fever as well as sniffles and other cold-like symptoms that aren’t caused by allergies.
In a pair of final guidances, released last week, the FDA urges drug sponsors to focus as much as possible on real-world settings when trying to determine ideal doses for proposed medicines. But hay fever, formally known as allergic rhinitis, is better known, so the agency says it’s taking a more precise approach to clinical trials.
Unlike hay fever, it’s harder to define and diagnose runny, stuffy noses that aren’t directly caused by allergies; typically, they can only be pinned down after allergies or other possible conditions (like the flu) have been ruled out. So the FDA stresses drug sponsors consider real-world conditions for their trials, from patient recruitment to dosing. They should also target the specific subtype of rhinitis – or symptoms – they hope to address, which may require them to run preliminary studies to narrow their scope.
Once they’re ready to go, the FDA says it will consider trial designs other than the traditional Phase I, II and III mold. For instance, the agency says that while it prefers sponsors to test under real-life conditions, it’s open to “alternative exposure models,” though the guidance doesn’t offer any specifics about other potential trial designs.
The guidance notes that sponsors should carefully monitor patients’ responses to scents and other irritants, especially in trials for potential treatments for vasomotor rhinitis — the most common form of non-allergic rhinitis — because some drug formulas have been known to change sensitivities to smells.
Generally, the FDA says that it would prefer at least two Phase III clinical trials for drugs aimed at treating seasonal and perennial nasal allergies, but that it would consider a single trial as long as it’s “adequate and well-controlled” and “demonstrates the safety and effectiveness of the drug.”
It urges sponsors testing a proposed seasonal allergy elixir to work quickly when randomizing patients in a trial “because this generally reduces variability in allergen exposure.” For drugs treating perennial allergies, it’s still best to test efficacy in the off-season to minimize the risk that seasonal allergies may pop up during trials.
As far as recruiting goes, the guidance says that sponsors should enroll seasonal-allergy sufferers with at least a two-year history of hay fever — and that participants shouldn’t start an immunotherapy or change their regular treatment or dose within at least a month of the trial. Patients with acute or chronic sinusitis, chronic asthma and/or a history of using corticosteroids, leukotriene modifiers (asthma drugs like Singulair) or long-acting antihistamines should probably be excluded from trials, the FDA advises.
Safety, of course, is paramount, so sponsors should conduct routine lab tests at least twice on potential participants to check such things as liver and kidney function — once at the initial screening for a Phase III trial and again at the end of the trial. They should also keep an eye on volunteers’ heart health, performing an EKG “early in clinical development,” the FDA recommends.
A drug’s safety profile should include at least six months of data from 300 or more trial participants and a year or more of data from 100-plus patients, with the overall patient database including at least 1,500 patients. An undefined “sufficient number” of volunteers should be given the maximum dose of the proposed drug during a clinical trial. For children, sponsors should add an additional three months’ worth of data for intranasal products and one additional month for those taken by mouth.
If sponsors are testing meds containing corticosteroids, they should screen adrenal function at least once before participants begin taking the candidate drug and at least six weeks after they start taking it, the guidance says. Sponsors should also be on the lookout for signs of cataracts and glaucoma, potential side effects of continued steroid use.
The FDA urges sponsors to proceed with caution if testing corticosteroids on kids — and perhaps skip oral prednisone trials in children. In any pediatric trials, the guidance recommends a six-week hypothalamic-pituitary-adrenal axis trial, a complex analysis of how glands are handling a new drug; it also encourages sponsors to get a pre-trial baseline measure to make sure proposed drugs aren’t stunting growth.
For topical meds, sponsors should give adult patients nasal exams — initially to establish baseline health and then to monitor potential side effects on the area being treated. The FDA reminds sponsors that they consider a topical drug’s delivery system as part of its review, meaning the whole product is being evaluated as a hybrid drug/device trial.
“Therefore, we recommend that all key trials in the development program, including dose-ranging trials and confirmatory efficacy and safety trials, be conducted with the to-be-marketed product,” the guidance says. “Depending on the nature and extent of the changes, the altered product may be viewed as a new product, necessitating a separate development program with efficacy and safety trials.”
Read the hay fever guidance here.
Read the non-allergic rhinitis guidance here.