SILVER SPRING, Md. -- An FDA advisory committee voted to recommend approval of amikacin liposome inhalation suspension (ALIS) therapy for the treatment of non-tuberculosis mycobacterial (NTM) lung disease as part of a combination antibacterial regimen in patients with limited or no treatment options.
Conversely, the committee voted against recommending the therapy for all adult patients with this type of lung disease.
The votes were virtually flipped for each question -- with the FDA's Antimicrobial Drugs Advisory Committee voting 12-2 to recommend approval in patients with limited treatment options, but 2-12 against recommending approval of this therapy in all adults with this type of disease.
A third question -- whether the surrogate endpoint of sputum culture conversion based on three consecutive negative sputum cultures is reasonably likely to predict clinical benefit -- split the committee almost down the middle, in a narrow 8-6 vote that agreed an inference could be made between the two.
In a spirited discussion session that went nearly an hour over the scheduled time, the director of the FDA's Division of Anti-Infective Products (DAIP), Sumathi Nambiar, MD, praised the committee for taking the extra time to allow for "a robust discussion" of complicated issues.
The sponsor, Insmed, submitted a new drug application under subpart H (accelerated approval) and was granted priority review under a Qualified Infectious Disease Designation. The FDA also noted it had "breakthrough therapy and orphan product designations."
The populations studied in the trials presented were patients with refractory Mycobacterium avium Complex (MAC), and the committee agreed that better therapies to treat this population were needed, that the therapy was clearly better than "background therapy," and that use of this drug may allow avoidance of prolonged use among patients on failing therapies.
With 13 public comments, including several from patients with this type of disease, committee members heard testimonials about the need for new therapies and in some cases, how much they had been helped by the amikacin therapy. One even called it "inhaled hope."
Committee member Henry Masur, MD, of the NIH Clinical Center in Bethesda, Maryland, characterized this as a "tremendously complex disease to study, with so many comorbidities and confounding factors."
"There's enough of a signal for efficacy, and enough of a signal that there's no major safety issue," he said. "We have to start somewhere."
One of the two "no" votes was from Peter Weina, MD, of Walter Reed National Military Medical Center, also in Bethesda, who said that he "wanted to vote yes," but worried about the potential for off-label use in the larger NTM population.
"This isn't a new product, this is repackaging of an old troublesome drug that's being used anyway. A statistical benefit isn't a practical benefit," he said.
But because the sponsor only presented trial results in a population with refractory NTM disease, more data need to be generated to make an assessment of benefit in this setting, he said.
"I don't see how no data could provide 'substantial evidence,'" said committee member Michael Proschan, PhD, of the Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), also in Bethesda.
Consumer representative Ellen Andrews, of CT Health Policy Project in New Haven, Connecticut, was one of the "yes" votes to recommend the product for all NTM patients. She argued that while there was no direct evidence on the question, it seemed reasonable that if it worked for a patient population where other therapies had failed, "it would work at an earlier stage."
Surrogate Endpoint Split Vote
As part of the accelerated approval process, the FDA explained that the trials were done based on a surrogate endpoint -- in this case, three successive negative sputum cultures -- a microbiologic endpoint used in American Thoracic Society (ATS) guidelines.
But the agency's staff seemed to question whether this endpoint provided enough evidence of clinical benefit.
"Does a microbiologic surrogate endpoint result in an improvement in how a patient feels, functions or survives?" DAIP clinical team leader, Peter Kim, MD, said. "It seems we are still wrestling with a final confirmatory endpoint that shows patients are improving how they feel, function or survive."
Ultimately, a slim majority of committee members drew the inference that the surrogate endpoint was reasonably likely to predict clinical benefit.
"The primary question the FDA is asking is whether or not achieving microbiologic cure likely results in clinically meaningful improvement in patients, asked in the context of evidence-based guidelines," said committee member Michael Green, MD, of the University of Pittsburgh School of Medicine in Pennsylvania. "At minimum, clearance of sputum leads to stopping what might be years of ineffective therapy."
But committee members who voted against accepting the surrogate measure cited the fact that sputum cultures aren't clinical outcomes, such as the 6-minute walk test -- where the agency found non-significant results at the 6 month follow-up visit.
"I interpreted the question -- 'likely to predict clinical benefit,' and data on clinical benefit was not provided," committee chair Lindsey Baden, MD, of Brigham and Women's Hospital in Boston, said.
Panel members recommended that future trials define a clinically meaningful endpoint in this population, such as patient-reported symptoms like quality of life, to address the issues raised during the discussion.