Washington Editor

SILVER SPRING, Md. - Members of the FDA's Oncology Drug Advisory Committee on Wednesday agreed with agency reviewers that two investigational products for cancer patients need more study before approval.

The panelists voted 12-2 that IDM Pharma Inc. has not demonstrated a substantially effective profile for Junovan (mifamurtide), and 7-2 that DOR BioPharma Inc. has similarly come up short for orBec (oral beclomethasone dipropionate). Junovan is under FDA review as a treatment for newly diagnosed, resectable, high-grade osteosarcoma following surgical resection in combination with multi-agent chemotherapy, and orBec is being evaluated as a treatment for gastrointestinal graft-vs.-host disease.

The agency typically follows the advice of its advisory committees.

Post Hoc Analysis Hinders Junovan

FDA reviewers questioned the strength of data underlying IDM's new drug application, citing discrepancies in case-report forms, inadequate patient follow-up and the use of post hoc analyses, particularly the exploratory quality of survival findings given that the study missed its primary endpoint of disease-free survival. The submission is based on the results of a Phase III study that was conducted by a cooperative group and admittedly not designed for regulatory submission.

But the company's analysis showed a six-year survival probability of 77 percent in Junovan-treated patients, compared to 66 percent in those who didn't receive it, translating into a one-third reduction in the risk of death. That represents "the first significant progress in the treatment of osteosarcoma in 20 years," said Paul Meyers of Memorial Sloan-Kettering Cancer Center.

So IDM, of Irvine, Calif., filed on the belief that the long-studied drug, whose rights have been controlled by several companies over the years, is of benefit in this rare disease with few treatment options. Such thinking isn't uncommon in unusual conditions like osteosarcoma, as conveyed by survivors during the meeting's open public session and physicians who spoke on IDM's behalf, all of whom suggested adjusting approval criteria in these types of cases.

Conceding the study's "limitations," Ian Lewis, of St. James University Hospital, said Junovan represents the next step toward a cure without adding safety burdens. "I want [the drug] to be available for my patients."

Adding it to existing treatment regimens could save 50 lives per year in the U.S., said Eugenie Kleinerman, of M.D. Anderson Cancer Center. "Consider the rarity of the disease and the unmet medical need," she said.

But the FDA reviewers clearly don't regard IDM's single-trial findings as compelling enough. "Substantial evidence is a high standard," said Patricia Dinndorf, a medical officer at the agency. That hurdle typically requires two studies.

A confirmatory study would take eight to 10 years, said Bonnie Mills, IDM's vice president of clinical operations, making it "impractical" and also "unethical," given the benefit seen in the previous study.

However, Lee Helman, of the National Cancer Institute, said it would be "unethical" to not substantiate the data with another trial.

IDM's stock (NASDAQ:IDMI) lost $1.30 Monday, or 32.5 percent, to close at $2.70. It closed Friday at $8.94, before the FDA review comments were first disclosed.

DOR Data Also Fail To Impress

DOR, of Miami, based its application for approval on Phase III data showing that survival 200 days after allogeneic hematopoietic stem cell transplantation produced a 66 percent reduction in mortality among patients randomized to orBec (p=0.0139); and a year after randomization, there were fewer systemic immunosuppressive side effects and a reduced treatment failure. Further, that mortality benefit was corroborated in a retrospective analysis of Phase II data in which there was a 55 percent reduction in mortality 200 days after transplant.

Gastrointestinal graft-vs.-host disease, a life-threatening complication of allogeneic hematopoietic stem cell transplantation, affects about 7,000 people per year in the U.S. According to the University of Washington's George McDonald, who spoke on behalf of DOR, orBec "addresses an unmet medical need" by controlling gastrointestinal graft-vs.-host disease without protracted steroid exposure, particularly prednisone. He concluded that its risk-benefit ratio "is strongly in favor of benefit" in those patients.

FDA reviewers differed, though, noting problems with pooled data from the two studies, design differences between the tests and a lack of bioequivalence data between different formulations used in them. In short, drawing efficacy conclusions leads to "difficulties," said Nancy Scher, a medical officer at the agency. "We believe that additional studies are necessary to demonstrate efficacy and safety."

Most panelists arrived at the same conclusion.

"If we lower the bar for this drug," said the University of Missouri's Michael Perry, "then we lower the bar for every other drug," later adding that "we simply need a better trial."

The FDA raised the possibility of compassionate use to accommodate patient needs.

DOR's shares (OTC BB:DORB) tacked on 5 cents, or 13.5 percent, to close at 42 cents. The stock had fallen 30 cents, or 42.9 percent, to close at 40 cents when FDA review documents were released Monday.