FDA releases draft guidances on developing rhinosinusitis drugs, colonoscopy bowel preps

Regulatory NewsRegulatory News | 14 December 2021 |  By 

The US Food and Drug Administration (FDA) has recently released two draft guidances: one with advice for sponsors on the development of drugs for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), and another offering efficacy and safety considerations for the development of bowel cleansing products for colonoscopy.
Guidance on CRSwNP drugs
The agency provided recommendations for sponsors involved in a CRSwNP drug’s development, including details on trial population, trial design, considerations for efficacy and safety, and issues specific to corticosteroids and drug-device combinations.
In terms of clinical trial populations, FDA recommended sponsors include participants with CRSwNP at least 12 years of age or older in adult trials “who reflect the characteristics of clinically relevant populations, including with regard to race and ethnicity, and should consider clinical trial sites that include higher proportions of racial and ethnic minorities to recruit a diverse study population.”
Participants should have ongoing bilateral nasal polyps as confirmed through a valid scoring system. Exclusion criteria for trials include participants who have received sinus or intranasal surgery, have recently had acute sinusitis or upper respiratory infection, a nasal cavity tumor, fungal rhinosinusitis, rhinitis medicamentosa, nasal septal deviation, antrochoanal polyps or “presence of another diagnosis associated with nasal polyps.”
Trial duration for CRSwNP drugs being considered for market authorization will depend on the therapy and “its expected mechanism of action” as well as the time to clinical benefit. In particular, trials assessing efficacy and safety of a drug with outcomes of reduced use of corticosteroids, surgery, and nasal polyp recurrence should be longer. “Because CRSwNP is a chronic disease, we recommend trials of at least 24 weeks, but ideally 52 weeks, in duration,” the agency wrote. Sponsors can consider trials of shorter duration for topical corticosteroids; however, this should be discussed with the review division in advance.”
Recommended primary endpoints for trials of CRSwNP include the assessment of how a treatment impacts both chronic rhinosinusitis and nasal polyps with a “a well-defined and reliable clinical outcome assessment (COA) measure” like the nasal polyps score (NPS) or nasal congestion score (NCS). “Demonstrating a treatment effect on both endpoints is necessary to support evidence of effectiveness,” wrote FDA. Secondary endpoints can include smell, patient-reported symptom scores, surgery and oral corticosteroid use, and imaging, the agency noted.
When evaluating safety, long-term safety data needs to be collected. FDA suggested sponsors measure efficacy endpoints long term, and that “a sufficient number of subjects” receive the highest dose of the drug intended for market during the trial phase. Trials of topical drugs should include safety monitoring with nasal baseline and serial examinations planned.
“Individual drugs may have variations in dose, dosing regimen, and systemic exposure; thus, their indications may need different testing procedures,” the agency wrote. “FDA encourages sponsors to contact the review division before carrying out corticosteroid-induced hypothalamic-pituitary-adrenal axis suppression assessments.”
Considerations for drug-device combinations of nasal sprays, pre-filled syringes, autoinjectors, and nasal sinus stents—a change in formulation, components of the device, excipients, or formulation flow path—“can alter the delivery characteristics and affect the clinical performance and user interface of the combination product,” FDA explained. “[W]e recommend that sponsors conduct all key trials in the development program, including dose-ranging trials and confirmatory efficacy and safety trials, with the to-be-marketed combination product.”
Guidance on bowel cleansing for colonoscopy
FDA’s recommendations for products intended to be taken prior to a colonoscopy for purposes of bowel cleansing focused on trial population, trial design, considerations for efficacy and safety, and a note on what the agency considers a fixed-dose combination product.
Inclusion criteria for clinical trials should include “a population that is sufficiently broad and inclusive to assess safety and efficacy across all relevant subgroups likely to use the product,” such as patients older than 65 years of age from representative ethnic and minority populations, FDA said.
Specific care should be given to selecting from groups of patients with chronic kidney disease, with an exception for including patients with stable chronic kidney disease not at risk for developing issues after using the bowel cleansing product. “Sponsors should provide adequate justification for including/excluding patients with different levels of kidney function based on the stage of product development, safety profile of the product, and understanding of the effect of kidney function on elimination of the product, if absorbed,” they said.
Trial design should a randomized, blinded, parallel-group design with an active comparator to assess non-inferiority. During Phase 3 trials, FDA recommends sponsors use a different active comparator “to best characterize the efficacy and safety profile of the new product.” When assessing outcomes, efficacy should be evaluated during colonoscope insertion but before washing and suction, and all colonoscopies should be recorded, the agency noted.
FDA recommends a primary endpoint of successful bowel cleansing as measured by an efficacy scale with categories of excellent, good, fair, and poor, with non-overlapping criteria. “Because adequate visualization of the entire colon is important, particularly in screening colonoscopy to avoid missed lesions, a score of fair or poor in any segment will result in the patient being considered a failure for the primary efficacy analysis,” the agency said. Secondary endpoints that should be considered include cecal/ileal intubation rate, time to reach cecum, proportion of participants in the “excellent” category, adenoma detection rate, and non-polypoid adenoma detection rate.
Participants of a clinical trial should be scheduled for in-person visits to evaluate vitals and blood chemistry at the time of randomization, the day of the procedure, and between 48 hours and 72 hours after the colonoscopy. Any participant with “clinically significant abnormal laboratory tests” identified during the post-colonoscopy site visit should also be scheduled for another site visit 7 days after the procedure.
FDA had a final note on what the agency considered a fixed-dose combination bowel cleansing product. “If the proposed study product contains two or more active ingredients, it would most likely be considered a fixed-dose combination product as defined in 21 CFR 300.50. Sponsors should meet with the Division regarding fixed-dose combination considerations early in the development process,” they wrote.
Chronic Rhinosinusitis with Nasal Polyps: Developing Drugs for Treatment
Bowel Cleansing for Colonoscopy: Efficacy and Safety Considerations for Developing New Products


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