Triferic’s Modified Indication Gets Past FDA Panel Despite Real World Applicability Concerns

Oncologic Drugs Advisory Committee endorses approval of Rockwell’s Triferic, but for only half of proposed indication; support tempered by “artificial” nature of Phase III studies, a claim to which Rockwell’s CMO agreed.

FDA advisors voted 8-3 in favor of approval for Rockwell Medical Inc.’s Triferic to treat iron loss in dialysis-dependent chronic kidney disease patients Nov. 6 despite lingering concerns that the company’s Phase III program was too different from real-world clinical practice to accurately predict the risk/benefit profile of the drug.

The Oncologic Drugs Advisory Committee nixed the second half of Triferic’s proposed indication, telling FDA additional studies were needed to support a claim that the drug reduces the prescribed dose of erythropoiesis stimulating agent (ESA) required to maintain desired hemoglobin levels. There was no formal vote on this part of the company’s indication.

Rockwell is seeking approval of Triferic (soluble ferric pyrophosphate) for the treatment of iron loss or iron deficiency to maintain hemoglobin in adult patients with hemodialysis-dependent stage 5 chronic kidney disease and to reduce the prescribe dose of erythropoiesis stimulating agent required to maintain desired hemoglobin levels. It has a user fee goal date of Jan. 24, 2015.

Approval without an ESA-sparing claim could hurt the drug’s commercial prospects. Rockwell has indicated it could compete against older and cheaper I.V. irons and penetrate the dialysis market because Triferic could decrease overall dialysis treatment costs by reducing the need for high amounts of ESAs, the costliest component of dialysis therapies (Also see "Triferic’s ESA-Reduction Claim Draws FDA Skepticism Ahead Of ODAC Review" - Pink Sheet, 4 Nov, 2014.).

Medicare Part B’s bundled payments for drugs and services related to end-stage renal disease would likely make an ESA-sparing product very appealing to prescribers (Also see "Rockwell Sees Opportunity For Triferic In Cost-Sensitive CKD Market" - Pink Sheet, 24 Mar, 2014.).

FDA indicated in advisory panel briefing documents that the Phase II “exploratory” trial conducted to support the ESA claim was not sufficient and at the advisory panel said that two well-controlled Phase III studies are usually required for such a claim to be in the label.

The agency was less transparent in both briefing documents and at the panel meeting on its feelings on the hemoglobin maintenance indication, though it pointed out a number of statistical issues with the Phase III trials, including a high rate of missing data that made validity and robustness of the efficacy data difficult to address.

Off-Label Standard-Of-Care Complicates Review

Most panel members felt that the company did show a benefit of Triferic on hemoglobin maintenance in the Phase III studies that compared the drug to placebo, but most added the caveat that in the real-world hemodialysis patients would be treated with intravenous iron not placebo, even though there is no FDA labeled-indication for maintenance treatment with IV iron.

The panel also pointed out that in clinical practice physicians would have leeway to provide patients with oral or IV iron supplementation and adjust the patients’ ESA doses, two things that were not allowed in the trial.

Many members seemed to give Triferic the benefit of the doubt, because they couldn’t envision how the company could have conducted a trial that compared Triferic to an off-label treatment and because they didn’t see a safety signal in the sponsor’s trial program.

However, some suggested further study might be warranted to examine longer term efficacy and safety as well as the benefit/risk profile compared to standard of care.

“Notwithstanding some of the trial design issues and a little bit of the artificial nature of the way they had to do the trial I thought the totality of the data supported a benefit for real unmet medical need. …And with regards to safety … I didn’t think that there was an adverse safety signal that mitigated that benefit,” Brain Rini, Cleveland Clinic Foundation, said.

“I think the conundrum here is that the trial design doesn’t reflect patterns of care but by the same token we can’t ask the company to have a control arm with a non-FDA approved indication and so is it better than placebo, yes. I don’t think we can say much more than that but I thought it proved the point of what they were trying to do in the confounds of that design,” Bruce Roth, Washington University School of Medicine, said.

“I think the study as was designed showed a benefit for the patients who received the treatment. My concern is that the actual use of the drug will be quite different than the data that was presented,” ODAC Chair Deborah Armstrong, added.

“On the other hand I’m trying to imagine a well-controlled randomized Phase III trial where you mandate what’s going on when the things you are going to mandate are not FDA approved,” Armstrong said.

She suggested further study would be warranted. “So I’m not even sure what the right trial design would be but it seems like … there needs to be some safety and potential efficacy studies looking at much more prolonged use of the agent. But for the very brief more limited question I thought the answer was yes.”

Rockwell Admits Lack Of Real-World Applicability…

When pressed by ODAC members regarding concerns of real-world applicability of the Phase III studies, Rockwell’s Chief Medical Officer Raymond Pratt acknowledged that the studies “are not the way anemia is managed in chronic dialysis units,” and that in the real-world ESA doses are continuously adjusted and iron can be given for maintenance or when patients require it.

But Pratt said the company couldn’t conduct its Phase III program in a manner that was more indicative of real-world practice because it had “to isolate the effect of Trifieric on hemoglobin to satisfy the regulatory requirement to show an effect of Triferic alone on the patient population.”

… And FDA Says I.V. Iron Comparison Was Possible

One panelist, who voted in favor of approval, said he disagreed with the comments that a randomized trial comparing Triferic to I.V. iron could not be conducted.

“I recognize that there is not an FDA approval for that but we have now heard for the last two decades nephrologists have been going ahead and giving IV iron on a maintenance basis anyway,” James Liebmann, University of Massachusetts, said. He added that such a trial “should be done.”

When the panel asked the agency’s opinion on the use of an off-label comparator, Ann Farrell, Director of FDA’s Division of Hematology Products concurred with Liebmann, that the agency believes a randomized trial comparing Triferic against I.V. iron could be conducted.

The FDA’s briefing documents released ahead of the advisory panel also indicated that Rockwell had submitted a Special Protocol Assessment for the pivotal studies, but the agency did not reach agreement on an SPA.