EMA finalizes clinical development guideline for new gout treatments
The EMA on Thursday issued a guideline setting its expectations for the clinical development of new urate-lowering therapies (ULT) and anti-inflammatory drugs to treat gout.
The 14-page guideline comes less than a year after the EMA’s Committee for Medicinal Products for Human Use (CHMP) released the draft version for consultation and seven years after the agency published a concept paper highlighting the need for such guidance.
While there are a handful of ULTs available in Europe, the EMA notes that there are some issues with existing treatments. “Allopurinol, a xanthine-oxidase inhibitor interfering with the production of uric acid, is considered as a first-line ULT treatment option … however, allopurinol hypersensitivity syndrome with skin reactions is quite common,” the EMA writes, noting that doses must also be lowered in renally impaired patients.
Within the guideline, the EMA provides recommendations for patient selection, safety and efficacy assessments and clinical trial design, as well as discussing considerations for studies in elderly, pediatric and renally impaired patients.
However, the EMA points out that “the study design, inclusion criteria, primary endpoints and trial duration largely depend on the treatment goal and mode of action of the new drug.”
The EMA notes that treatment guidelines in both the US and EU do not endorse the treatment of asymptomatic hyperuricemia and says that its clinical development guideline does not address the treatment or prophylaxis of acute hyperuricemia caused by other conditions.
When selecting patients for enrollment in clinical trials, the EMA recommends that sponsors use established diagnostic criteria, such as those developed by the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR).
The EMA says that sponsors may distinguish “between patients with intermittent flaring disease, with symptom free intervals, or advanced patients with chronic arthropathy manifestations,” and recommends that studies for ULTs select patients with hyperuricemia above 7mg/dl as a baseline.
The agency also encourages sponsors to enroll patients with common comorbidities, such as obesity, diabetes, hypertension and renal impairment … depending on the safety profile of the drug.”
The EMA points out that there are different potential treatment goals for gout which require different clinical development plans and trial designs, such as the reduction of hyperuricemia and urate crystal load or the symptomatic treatment of acute gouty arthritis flares.
The EMA recommends that for ULTs, sponsors conduct parallel, randomized double-blind placebo-controlled trials for at least six months. For first line treatments, the EMA says that at least one study should use allopurinol as an active control, while the agency provides different options for study design for second line treatments depending on whether the drug will be used as monotherapy or in combination with a xanthine oxidase inhibitor (XOI).
The EMA recommends using serum uric acid (SUA) as a surrogate endpoint to evaluate the efficacy of ULTs. “As it takes time for the body to be cleared of uric acid crystals, and as uric acid levels fluctuate over time depending on food and fluid intake, the primary endpoint should not consist of SUA levels at a single time-point, but should reflect a sustained SUA response below a critical target level. SUA should, therefore, be frequently monitored in the trials (at least every 4 weeks),” the EMA writes.
The primary endpoint for confirmatory trials for ULTs should be sustained SUA levels below 6mg/dl for three consecutive months or < 5 mg/dl for patients with tophaceous gout.
For anti-inflammatory drugs, the EMA also recommends parallel, double-blind randomized placebo-controlled trials, though the agency says that “no placebo-control is needed if the study objective is demonstrating superiority towards an active control.” For non-inferiority studies, the EMA says a three-arm study including a placebo is generally necessary.
For anti-inflammatory drugs, the EMA offers different endpoints depending on the goal of treatment, such as acute treatment of flares or prophylaxis at the start of ULT.
RAPS: First published in Regulatory Focus™ by the Regulatory Affairs Professionals Society, the largest global organization of and for those involved with the regulation of healthcare products. Click here for more information.