An FDA advisory board recommended the agency approve a fecal microbiota transfer (FMT) product for recurrent Clostridium difficile infections.
By a vote of 13-4 on Thursday, the Vaccines and Related Biological Products Advisory Committee (VRBPAC), said RBX2660 was effective for treating patients with recurrent C. diff infections who failed first-line antimicrobial therapy. Safety landed in favor of the product as well, by a vote of 12-4 (there was one abstention).
RBX2660 is a microbiota suspension prepared from human stool, which is collected from pre-screened, qualified donors and administered rectally by enema.
Members of the committee were not necessarily swayed by strong data, but rather because of the strong need for treatment options in C. diff, which affects about half a million people in the U.S. each year, according to the CDC.
“This is better than what we have,” said temporary VRBPAC voting member Clifford McDonald, MD, of the CDC in Atlanta, who voted in support of the product.
No approved options are currently available for patients failing first-line antimicrobial therapy. The only subsequent treatment is giving more antibiotics, which can lead to additional recurrences and increased antibiotic resistance.
“I’m sympathetic to the unmet need for this condition,” said Dean Follmann, PhD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who voted in support of the product.
Other members were swayed by the rigorous screening protocols laid out by developer Rebiotix.
We have a really “tortured” protocol to make sure we are not transferring pathogens, said Paul Offit, MD, of the Children’s Hospital of Philadelphia, who voted yes for safety and efficacy. “That’s the biggest advantage here.”
“The real goal here is to provide a standardized product and process for consistent efficacy and safety,” said Eric Rubin, MD, PhD, of Brigham and Women’s Hospital in Boston, who also voted yes.
Rebiotix’s application for approval included five studies in its clinical development program for the FMT product, all with at least 6 months of follow-up — a pair of phase III trials (one randomized) and three phase II trials.
The primary efficacy analysis for the randomized phase III trial used a Bayesian analysis that borrowed information from one of the phase II studies, due to enrollment challenges that prevented two placebo-controlled phase III trials from being conducted.
The randomized phase III trial supplying the main support for RBX2660 — Study 2017-01 or PUNCH CD3 — enrolled 289 subjects with recurrent C. diff and assigned them in a 2:1 ratio to the FMT treatment or placebo. The combined data with the earlier trial demonstrated a success rate of 69% with RBX2660 (95% CI 0.63-0.76) compared to 57% with placebo (95% CI 0.47-0.67). Success was measured as absence of C. diff diarrhea, meaning three or more uniform stools in 24 or fewer consecutive hours for at least 2 consecutive days for 8 weeks.
But while the analysis met the success threshold considered equivalent to a positive well-controlled trial, according to FDA staff, it did not meet the threshold for a statistically very persuasive finding from a single trial that could in effect substitute for positive evidence from two well-controlled trials.
The integrity of the efficacy data was at the center of lively debate, with agency staff noting that the results did not show a statistically significant advantage for RBX2660, while the sponsor cited the difference as clinically meaningful.
It was also determined that the analysis was not prespecified. Charts, data, explanations covering a dozen slides explained how the data was moved from one analysis to the other.
“If you torture the data enough it will confess to almost anything,” said Jay Portnoy, MD, of Children’s Mercy Hospital in Kansas City, who voted against recommending approval.
Concerning the safety, Portnoy was skeptical about the dismissal of 18 deaths (2.4%) in the study group, compared to none in the placebo group.
“We don’t know what changes to the gut microbiome does to your risk of having a heart attack or a stroke or dying from some other reason,” he said.
Safety analyses were derived from pooled data on 749 patients in the clinical program who received at least one dose of RBX2660 and 83 patients given placebo.
Overall, treatment-emergent adverse events (TEAEs), reported in 69.6% in the pooled RBX2660 data set versus 60.2% in the placebo group, tended to be mild or moderate in nature. Common TEAEs included abdominal distension or bloating, rectal bleeding, irritation or pain, chills/severe shivering, abdominal pain or cramping, increased diarrhea, constipation, nausea, vomiting, and fever.
Serious TEAEs were recorded in 14.2% of the RBX2660 patients and 7.2% of the placebo patients.
While the FDA is not required to follow the advice of its advisory committees, it usually does.