FDA offers advice on developing drugs for endogenous Cushing’s syndrome

The US Food and Drug Administration (FDA) said it is appropriate to use placebo arms in clinical trials when developing drugs to treat endogenous Cushing’s syndrome, despite ethical concerns raised by some stakeholders. The agency argued that using placebos is acceptable if sponsors have safeguards in place to reasonably protect trial participants.

FDA published a draft guidance on 8 September that outlines the agency’s thinking in developing drugs for endogenous Cushing’s syndrome, a rare condition in which the body overproduces glucocorticoids, to treat patients who are not candidates for surgery or for whom surgery has not been effective. The guidance only addresses endogenous forms of the condition and does not touch on exogenous Cushing’s syndrome, where the condition is caused by external factors such as overexposure to corticosteroids.

“This guidance is intended to focus continued discussions among FDA’s Division of General Endocrinology, pharmaceutical sponsors, the academic community, and the public,” said FDA. “This is the first guidance drafted by FDA on this topic.”

The agency notes that only 49 people out of a million are diagnosed with endogenous Cushing’s syndrome in the US each year. It includes adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent subtypes, of which 4-in-5 cases are of the latter type.

According to FDA, sponsors developing a drug for endogenous Cushing’s syndrome should focus on evaluating the pharmacokinetics and pharmacodynamics of their drug, dosing response and establishing the safety and efficacy profile. The agency said the dosing selection for the phase 3 trial of the drug should be based on dose-response, pharmacokinetics, pharmacodynamics and safety and efficacy data determined during the phase 2 trial. It also recommended other pharmacology studies, such as those assessing drug interactions and evaluating pharmacokinetics and pharmacodynamics, should be conducted early so they can help researchers mold future studies.

“In Cushing’s syndrome drug development programs, approaches to establish substantial evidence of effectiveness include two adequate and well-controlled trials or one adequate and well-controlled trial plus confirmatory evidence,” said FDA. “In certain cases, a well-designed and executed phase 2 trial can serve as one of the adequate and well-controlled trials.”

“Phase 3 trials should be randomized, double-blind, and placebo- or active-controlled,” the agency added. “An extension phase of at least 6-month duration should follow to obtain durability of response and long-term safety data.”

Asking for a placebo or active-controlled trial may seem controversial and raise ethical questions if it means depriving patients of a life-saving treatment, but FDA said it’s acceptable if safeguards are in place.

“Although some stakeholders have raised concerns about the ethics of a placebo control, this design is regarded as acceptable because monitoring and timely control of Cushing’s syndrome–related comorbidities during the trial (e.g., with antidiabetic drugs and antihypertensive drugs) and other protocol safeguards (e.g., inclusion and exclusion criteria, withdrawal criteria) can ensure the safety of subjects,” said the agency. “Limitation of the trial duration in a placebo-controlled trial can minimize other disease-related impacts, including osteoporosis, infection, and muscle loss.”

For active-controlled trials, FDA said sponsors should use a US-approved drug in its comparator arm that follows the recommended dosing for the specific patient population. The agency also said that sponsors should consider using a double-dummy trial design if the experimental drug and the comparator drug have different routes of administration or regimens.

The guidance further details FDA's thinking on proper efficacy endpoints, safety considerations, and statistical considerations, which is especially important since the patient population is so small.

Stakeholders can comment on the guidance on www.regulations.gov under docket no. FDA-2023-D-3518 until 7 November.

Guidance

FDA offers advice on developing drugs for endogenous Cushing’s syndrome

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