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By Donna Young
Washington Editor
The FDA is re-evaluating the appropriateness of using noninferiority trial designs for anti-infectives used to treat community-acquired pneumonia (CAP), which could affect firms like Woodridge, Ill.-based Advanced Life Sciences Holdings Inc., whose new drug applications are in the works.
The agency next week will ask an advisory panel to consider clinical trial designs in antibacterial studies for the CAP indication and to help the agency determine an appropriate noninferiority margin for active-controlled trials.
Regulators issued draft guidance on the use of active-controlled noninferiority studies for approval of antibacterial agents in October "to further articulate FDA's thinking regarding appropriate clinical study designs to evaluate antibacterial drugs," the agency said in documents.
Clinical trials of new antibiotics for CAP in recent years have tested the hypothesis that the drugs were not inferior to established antibiotics by a prespecified margin. But the FDA has initiated a re-evaluation of the appropriateness of a noninferiority trial design for CAP.
Regulatory uncertainty about an appropriate trial design has contributed to drugmakers' skittishness about pursuing new anti-infectives, the Infectious Diseases Society of America (IDSA) said in advisory meeting briefing documents posted Wednesday on the FDA's website.
"In turn, industry uncertainty about regulatory standards has exacerbated the already fragile market for antibiotic research and development," the group contended.
The current ambiguity in acceptable designs for clinical trials of CAP, IDSA asserted, "is contributing to disincentives in the discovery and development of new drugs for CAP."
"This crisis will be mitigated by the rapid approval and dissemination of clear and defensible guidelines for future clinical trials of new antibacterials for the treatment of CAP," the group urged.
About 30 drugs are approved by the FDA to treat CAP, the leading cause of illness and death in the U.S., and its predecessor indication, lower-respiratory tract infection. Only 10 of those products are oral medications.
Abbott Park, Ill.-based Abbott's Biaxin (clarithromycin) is considered the standard of care for the treatment of CAP. About 4 million to 6 million cases of CAP occur each year in the U.S., with 1 million episodes occurring in adults 65 or older.
The total cost of CAP to the annual U.S. health care budget is more than $10 billion, according to IDSA.
The group submitted to the FDA the outcomes of recommendations it gathered during a January industry workshop, which IDSA co-sponsored with the agency.
The FDA's Anti-Infective Drugs Advisory Committee at a two-day April 1-2 meeting is expected to review the workshop outcomes before voting on several questions related to the use of noninferiority studies for CAP.
Included in the IDSA's recommendation package is a suggestion for the use of noninferiority trials with an endpoint of 15-day all-cause mortality.
That recommendation could affect Advanced Life Sciences' new drug application for cethromycin, said analyst Matthew Osborne, of Lazard Capital Markets.
While the firm likely captured all-cause mortality at day 15, Osborne said, it is unclear if cethromycin's noninferiority margin is sufficient, 5 percent per IDSA's recommendation vs. 10 percent for cethromycin. However, he noted, the 5 percent is only a guideline.
Further, Osborne said, it is unclear if the FDA will accept mortality prospectively defined as a component of clinical failure, as in the cethromycin trials, rather than prospectively defined as a primary endpoint in a hierarchical endpoint or as a composite primary endpoint as proposed in the briefing documents.
According to Osborne, "IDSA does not say that mortality must be a component of a composite but that there are advantages of having it in there, that if it is a problem one could argue just for morbidity endpoints," a positive for Advanced Life Sciences.
For morbidity endpoints such as fever, Osborne said, "it is unclear if management controlled for anti-pyretic use as well as prospectively defined duration of normal temperature required to achieve defervescence."
He noted that the firm plans to hold an April 10 call to discuss the outcomes of an April 7 meeting with the FDA, where regulators are expected to provide "further clarity on these items and timelines required to conduct further statistical analyses, if at all."
Cethromycin met its primary endpoint in two pivotal Phase III studies. (See BioWorld Today, Nov. 16, 2007.)
The primary endpoints for the two Phase III studies, known as CL-05 and CL-06, was the clinical cure rate at the test-of-cure visit, days 14-21 after the start of dosing.
The incidence of adverse events was not statistically different between cethromycin and Biaxin in both trials, with mild-to-moderate diarrhea, headache, nausea, vomiting, abdominal pain and taste disturbance being the most commonly reported adverse events.
No drug-related serious adverse events were observed in either study.
The drug also is being investigated as a prophylactic postexposure treatment for inhalational anthrax, for which it has gained orphan drug status.
Shares of Advanced Life Sciences (NASDAQ:ADLS) rose 1 cent Wednesday, to close at 80 cents. | 
