The Long Tail of a Clinical Trial

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The mortality curves separate. (From Goodin et al. poster)

To conduct a clinical trial of a new drug, the researchers need to pick an ending: a place where the experiment will be stopped and the results between those taking the drug and those who haven’t can be compared. If the drug is a clear improvement, the trial will be stopped, and patients in the control group will be allowed to start taking the newly-proven treatment. Follow-up studies may then be difficult to conduct, particularly if the disease is too deadly or the patients are too hard to track.

So when almost every single member of a landmark study can be tracked down more than 20 years after its completion, that’s an impressive feat. Even more so when comparing the treatment and control groups two decades later reveals an unexpected, and very meaningful, long-term benefit. A new study, co-presented at two recent meetings by Anthony Reder, professor of neurology at the Medical Center, reveals that a multiple sclerosis drug first tested here 23 years ago continues to show benefits in patients on perhaps the most important outcome of all: mortality.

Interferon-β-1b was the first drug proven effective in slowing the progression of MS, based on a trial of 372 patients conducted at the University of Chicago and 10 other centers from 1988 to 1993. When the FDA approved the drug in 1993, its effects on quality of life were emphasized by Barry Arnason, professor of neurology and one of the study’s lead investigators, who told the New York Times that “People are going to stay on their feet longer, work longer and be happier.”

The researchers could not have anticipated that the drug might also help MS patients live longer as well. But when follow-up data was collected 16 years after the trial’s completion, a promising hint emerged. Researchers successfully re-established contact with 88 percent of the original subject pool for a paper in the journal Neurology, and confirmed the long-term safety of interferon treatment – their primary goal. But a secondary finding also attracted interest. Of the 328 patients contacted from the original trial, 35 had died, but only 6 of those were from the original high-dose interferon group, vs. 20 from the control group.

Because patients in the control group were also placed on interferon treatment after completion of the trial, the result suggested that starting interferon earlier had long-term benefits on mortality. But to confirm the effect, the researchers had to find even more patients from the original study, alive or deceased. For the 21-year follow-up, they expanded the coverage to an astonishing 98.4 percent of the original subject pool, lacking information on only 6 of the original patients.

Fortunately, the larger dataset confirmed the earlier promising hints on mortality. As presented at the American Academy of Neurology Meeting this month by Reder and neurologist Douglas Goodin of UCSF, patients who received interferon during the 1988-1993 trial were less likely to have died at the time of the follow-up. Of 81 patients who had passed away in the 21 years since the trial, nearly half were originally in the placebo group, meaning they had started interferon treatment roughly 4 years later than those enrolled in the two treatment groups. Remarkably, even those who had received interferon in the pivotal trial weren’t started on the drug until an average of 8 years after MS symptoms first appeared, much later than current clinical standards, Reder said.

“Even stacking the deck against us by relatively late treatment, and accounting for a follow-up period where all of the people were on the best possible medicine for them, we still see this huge difference,” Reder said. “We think this means there’s a very important survival effect of interferons.”

Since the approval of inteferon, more drugs have joined the clinician’s arsenal against multiple sclerosis. But none of these newer drugs have the history that allows for this kind of long-term study, Reder said. Some mysteries remain: both the low and high doses of interferon given in the original study appeared to have similar effects on reducing mortality, and no biological mechanism for the “early-start” effect exists at this time. But the data is an important reminder about the urgency of starting MS treatment early in newly diagnosed patients, Reder said.

“A lot of doctors and patients are nervous about the diagnosis at the beginning,” he said. “This is a life-changing diagnosis about a chronic disease, and there are two choices: you can deny you have it for a while until you have another attack, or decide to treat it early and have fewer symptoms in the future.”

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Reder, A., Ebers, G., Traboulsee, A., Li, D., Langdon, D., Goodin, D., Bogumil, T., Beckmann, K., Konieczny, A., & , . (2010). Cross-sectional study assessing long-term safety of interferon- -1b for relapsing-remitting MS Neurology, 74 (23), 1877-1885 DOI: 10.1212/WNL.0b013e3181e240d0

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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