The April 6 letter, published online this week by the federal safety watchdog, stems from an inspection that began exactly a year ago of a Plymouth, Minn., Entellus plant that the FDA conducted to review the company’s procedures in sponsoring the pediatric Xpress study.
The inspection found “serious violations” of regulations covering investigational device exemptions and the protection of human subjects, involving use of the Xpress dilator in patients under age 12 in frontal and sphenoid sinuses; the trial’s approved protocol only allowed treatment in the maxillary sinus for patients that young, according to the letter. The agency said it expressly denied an Entellus request to expand the trial protocol during a May 13, 2014, conference call and later told the company that any data from off-protocol use could not be used to back a marketing application for frontal and sphenoid treatment in the under-12 cohort.
“Yet, 18 out of 33 pediatric subjects received balloon sinuplasty treatment on the frontal and sphenoid sinuses. One clinical investigator performed 11 planned protocol deviations, a second clinical investigator performed 6 planned protocol deviations, and a third clinical investigator performed 1 planned protocol deviation,” according to the letter.
“We stated our concerns for higher risks of injury in children 2-12 years old due to absent or incomplete anatomical development,” the FDA wrote. “However, your staff still did not secure investigators’ compliance and pediatric subjects continued to be treated off-protocol after receiving these communications.”
The off-protocol use risked serious medical complications including cerebrospinal fluid leaks, intracranial complications and meningitis, the agency said, adding that Entellus also failed to report six of the off-protocol uses in patients ranging from age 2 to age 8.
The FDA said an October 2016 response from Entellus was inadequate.
“You did not consider the safety concerns stated by the FDA and did not adhere to your statement in your June 19, 2014 response in which you stated that patients 2-12 years old will have treatment limited to the maxillary sinus (es) only. Two subjects, under the age of 12, were enrolled in the study and received treatment of the frontal and sphenoid sinuses after your receipt of the safety concerns from the FDA. Additionally, neither of the informed consents mentioned in your response contained the additional risks associated with the change in treatment resulting from the protocol deviations. The parents/guardians awareness and acceptance of the additional treatment should have been confirmed and documented in a signed consent form that included a description of risks such as Cerebrospinal Fluid leaks, intracranial complications, and meningitis,” according to the letter.