01-May-09 13:11 Merck Serono's cladribine should be tested against active comparator in Phase III trials, neurologists say
Story Merck Serono's cladribine should be compared to an active comparator in Phase III trials for multiple sclerosis (MS) as opposed to placebo, neurologists at the American Academy of Neurology said.
According to Phase III data from the pivotal CLARITY study, patients in the cladribine treatment groups had a statistically significant reduction in the annualized rate of relapses compared to placebo. Patients treated with low-dose cladribine experienced a 58% relative reduction in annualized relapse rates with respect to placebo. Patients in the high-dose regimen group experienced a 55% relative reduction in annualized relapse rates with respect to placebo.
Novartis'(NYSE:NVS) FTY-720 was compared to Biogen Idec's (NASDAQ:BIIB) Avonex in the Phase III TRANSFORMS study. Genzyme's (NASDAQ:GENZ) Campath was also compared to high dose interferon in a Phase II study.
The FDA will look for registrational trials that go head-to-head with an active comparator rather than placebo controlled trials in MS, said Dr Michael Racke, professor and chairman of neurology at the Ohio State University Medical Center. This sort of trial is necessary to show dramatic efficacy, and superiority trials will also be crucial for getting the trial done in a reasonable amount of time, he said.
There is a shift towards using an active comparator instead of placebo, said Dr Hans Peter Hartung, professor and chairman of University Hospital Dusseldorf. The shift is from both from a regulatory and ethical standpoint, he said. Regulatory agencies should be in line on this issue, Hartung said. Furthermore, there are many Phase II drugs that are tested against a placebo when an active agent is available as a comparator, he added.
Despite the fact that cladribine has been tested against placebo, the biggest issue is that Merck-Serono is filing for approval based on one trial, Hartung said. The FDA and EMEA may suggest a second trial against an active comparator and give conditional approval, he speculated.
Dr AM Rostami, chair of the department of neurology at Thomas Jefferson University, said the ethical factor is a major impetus for active comparator trials, because the rationale is that there are already effective medications available that show a 30-50% reduction in attacks. It is not ethical to deny patients an effective treatment and an active comparator is require to effectively compare the tested agents, he said.
Dr Clyde Markowitz, the local principal investigator for several national and international clinical trials of new and combination MS therapies and assistant professor in the department of neurology at the University of Pennsylvania, was hesitant to say whether or not cladribine could receive approval based on one study.
Still other neurologists, such as Rostami, said if there is significant preclinical, Phase I and Phase II data, then a multicenter trial, if done adequately with good outcome measures could be enough for approval.
Merck-Serono could not be reached for comment.
Dr Mark Tullman, director of the Multiple Sclerosis Clinical Care and Research Center at Columbia University, said there are several ongoing trials that have active comparator arms. "We have head-to-head FTY720 versus Avonex. Cladribine was a placebo controlled trial," he added.
Biogen's BG-12 has a placebo arm, but also a Copaxone arm. Teva's (NASDAQ:TEVA) laquinimod has a placebo as well as an active arm. Campath is going head-to-head versus Rebif, Tullman said. "One needs to know how much better any given new therapy is, compared to the currently available therapies," he added.
"It's an FDA issue. Placebo controlled trials are still being done and can be done. It's the ethics of placebo controlled trials," he said.
Dr John Richert, executive vice president of research and clinical programs at the National Multiple Sclerosis Society in New York, said the current measures used in trials tend to fall short of what is needed to evaluate therapies effectively.
One of the dilemmas these days are clinical trial designs and outcome measures are not as useful as they were 10-15 years ago, Richert said. Back when companies could conduct reasonably large long-term studies of a drug versus placebo alone, clinical trial design was much easier, he said. "Now that it's not ethical in most locations to conduct a trial against placebo only, we're challenged a lot more in terms of head-to-head trials," he added.
"We already have drugs that are very beneficial. Don't give up on the current drugs yet, and look at the new drug's safety profile before making a decision," said Dr Jack Burks, clinical professor of neurology at the University of Nevada.
by Elizabeth Krutoholow and Kimberly Ha in Seattle
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