FDA advisory committee members backed accelerated approval of Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid) for primary biliary cirrhosis but suggested modifications to an ongoing confirmatory trial, as well as additional post-marketing studies, may be needed to address uncertainties left in the wake of the lone Phase III trial.

At an April 7 meeting, the Gastrointestinal Drugs Advisory Committee voted 17-0 that there is substantial evidence to support accelerated approval of obeticholic acid (OCA) for the treatment of primary biliary cirrhosis (PBC) in combination with ursodeoxycholic acid in adults with an inadequate response to the latter drug or as monotherapy in adults unable to tolerate UDCA.

The committee members generally agreed that reduction in alkaline phosphatase (ALP) could be used as a surrogate endpoint reasonably likely to predict clinical benefit in the treatment of early-stage PBC, although some panelists said that total bilirubin levels also should be considered in assessing a drug's effect.

Analyses of the Phase III trial by Intercept and FDA showed that relative to placebo, a statistically significant proportion of patients in both OCA treatment groups achieved ALP reductions.

"I do have a concern about using surrogate endpoints," said Michael Proschan, mathematical statistician at the National Institute of Allergy and Infectious Diseases. However, "I was persuaded that the evidence was strong enough, and [relied] on the medical experts as well to convince me that it has an effect."

Several panelists pointed to the rarity of the disease and its associated unmet need as support for accelerated approval. UDCA is the only approved treatment for PBC.

"Alkaline phosphatase is reasonably likely to predict clinical benefit, and there's no significant tolerability concerns with the dose proposed," said Marina Silveira, a gastroenterologist and liver transplant specialist at the Louis Stokes Cleveland VA Medical Center. "I do think there are more studies that are going to be needed to be carried out" before regular approval.

Concerns About Historical Controls, Recruitment

Panelists generally said there was sufficient evidence to support OCA's use as monotherapy and that the proposed dosing regimen was appropriate.

Panelists were split on whether the Phase III data supported use in moderately advanced and advanced stages of PBC, but they generally said the data were insufficient to support use in moderately advanced and advanced cirrhosis (Child-Pugh B and C).

After the voting question on accelerated approval, the panel focused its attention on Intercept's ongoing confirmatory study. In briefing documents released ahead of the meeting, FDA suggested some aspects of the trial might need tweaking, particularly with regard to patient enrollment criteria and extent of monotherapy use in the trial ([A#14160405003]).

The global confirmatory trial aims to enroll 350 patients, representing a more advanced disease population than was seen in the pivotal trial, according to the company. The primary composite endpoint is all-cause death, liver transplant or events related to end-stage liver disease.

While the trial has been designed with a placebo control, there also is a historical control in place in the event that there are enrollment difficulties after OCA is approved due to patients' reluctance to be randomized to a placebo arm. Intercept is targeting a total number of 121 events, which will provide 80% power to demonstrate statistical significance with a hazard ratio of 0.60, Intercept VP-Clinical Development Leigh MacConell said.

Linda Robertson, VP-regulatory affairs and quality assurance, said although Intercept started the study in 2014 and 73 patients have been randomized, the company remains in discussions with FDA as to whether a modified design or protocol amendments may result in a stronger confirmatory trial.

Several panelists raised doubts both about the company's ability to enroll such a study to completion after OCA is approved and about the alternative use of historical controls. "The use of historical controls is a non-starter," said Timothy Lipman, emeritus chief of the GI-Hepatology-Nutrition Section of the Department of Veterans Affairs Medical Center in Washington, DC. "That makes it a lower quality study."

"I'd be concerned with the fact that if the medicine is approved, which I assume it will be, then I think it's going to be a disincentive for people to participate in clinical trials, especially where there's a placebo arm," Lipman continued. "That's going to be very difficult to recruit patients."

"The FDA is always concerned about this issue when we use accelerated approval," said Lara Dimick-Santos, cross-discipline team leader in FDA's Division of Gastroenterology and Inborn Errors Products. "One of the biggest drawbacks to using accelerated approval is the retention of patients in a placebo-controlled trial after approval."

Dimick-Santos noted that if FDA approves OCA in the near term, it would become the first regulator to do so, with the European Medicines Agency likely to be the second.

There are several countries where approval may be many years down the road, Dimick-Santos said, "so hopefully at least some placebo patients can be maintained" in the global confirmatory study.

Enrollment Criteria

The confirmatory trial's biochemical enrollment criteria – which are based on total elevated bilirubin or elevated ALP – may result in a patient population comprising primarily early- and moderate-stage disease, but not advanced disease, Dimick-Santos said, raising this as another concern.

Silveira suggested requiring that a certain proportion of patients meet the bilirubin enrollment criteria, thus ensuring that patients have more advanced disease than those enrolled in the Phase III study. She also suggested a 2:1 active-to-placebo randomization scheme as an inducement for patients to enroll.

However, biostatistician Susan Ellenberg, University of Pennsylvania, raised concerns about a 2:1 randomization and, instead, suggested a better incentive would be some type of crossover mechanism in the event that patients experience significant adverse changes in ALP or bilirubin.

Miriam Vos, pediatric hepatologist from Emory University, suggested that patients with more advanced disease might be better studied in a separate trial, such as a shorter, dose-ranging study, so as to avoid "putting too much on one trial."

Some panelists also suggested a need for greater attention to cardiovascular parameters in the confirmatory trial given the occurrence of HDL-cholesterol decreases in patients taking OCA.

Patient representative Donna Cryer said FDA and Intercept should take a list of the committee's concerns and prioritize them in determining which are the most feasible to address in the ongoing confirmatory trial.

The drug's May 29 user fee goal date means FDA and Intercept will have less than two months to negotiate final details about post-marketing studies if the agency follows the panel's advice on accelerated approval ([A#14160223002]).

Intercept's Cirrhosis Endpoint Gets FDA Panel Nod For Accelerated Approval

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