A 5,000-patient observational cohort study included in Tysabri's risk management plan for return to market may need an internal control group to provide useful results, members of FDA's Peripheral & Central Nervous System Drugs Advisory Committee indicated March 8.

"To me, the observational study as it is currently designed, I don't think it's going to provide useful information in the absence of a control," committee member Michael Hughes (Harvard School of Public Health) said.

"Maybe instead of the observational studies there should be randomized trials which seek [to answer] questions of interest," he suggested.

"The alternative is to have a non-randomized control group in this particular study," the biostatistician said.

Committee member Larry Goldstein (Duke University) called objectives of the observation study "unclear."

Referring to the committee's debate on first-line use of Tysabri (natalizumab) in relapsed multiple sclerosis patients, Goldstein maintained that "I'd rather the effort be put in to answer the question that's of direct relevance and importance, which in my view would be that head-to-head comparison as first-line therapy."

The committee split on whether first-line use with Tysabri was warranted.

Biogen Idec VP-Drug Safety & Management Carmen Bozic maintained that including an internal control group in the observational study would be difficult.

"In terms of getting an internal control group" in the observational study that is based on a patient registry, "part of the issue with that is number one, it's a practicality issue," Bozic said.

"If you think about it, Tysabri-treated patients will be quite motivated to enter this type of study, where as patients on other treatments may see less of a reason," Bozic said.

She added that "an internal control group will actually not be that helpful because you may have different patients being treated with Tysabri" than with other MS drugs.

"Doctors may choose to use Tysabri in a different way and in different types of patients regardless of the indication statement and that may influence the safety profile," she said.

"You will still have difficulty interpreting the data," Bozic asserted.

Biogen Idec's observational study will enroll 5,000 patients (3,000 in the U.S.) from the Tysabri registry. The patients will be followed for five years.

All serious adverse events and information on use of immunomodulatory and immunosuppressant therapies will be collected in the study.

The study is designed to assess risk of serious infections and malignancies, and investigate potential signals of unanticipated adverse events. Detection of rare events down to an incidence of 0.06% is powered into the study.

Bozic said that Biogen Idec is proposing an external control group to be used for the cohort study.

"For example, we could go back to the clinical trial data...and ask the question: If malignancies are occurring at a certain percentage rate in the clinical trials, now at what rate are they occurring in the clinical practice setting and over the long term?" Bozic said.

The company could also use information from existing adverse event databases.

"We could also go back to other databases, like the [Spontaneous Adverse Event Reporting System] database and ask, 'are rates of events from malignancies over the long term with natalizumab what we would expect based on SAERS?'"

Hughes also questioned whether the study would be adequately powered to detect differences in adverse events.

Bozic responded that the study is "fully powered to address really very small differences that might occur between clinical trial setting and in the clinical practice setting." The study will be able to detect a 1.5% relative risk, or a 1.5-fold increase in events, she said.

At the Cowen & Co. Annual Healthcare Conference in Boston, Biogen Idec Exec VP-Development Burt Adelman noted that the details of the observational study have not yet been finalized.

"We don't know the details of what we'll actually be doing until we're done with our discussion with the FDA," he said.

Adelman noted that study will be a "proactive view of pharmacovigilance to understand other outcomes, many of which we think we already know about, that may be associated with long-term use of Tysabri to further refine the data that we will have in the package insert."

The Biogen Idec exec urged analysts to get comfortable with the idea of long-term post-marketing safety studies for products that receive accelerated approval or quick reviews.

"Get used to it guys," Adelman said, "this is going to be part of the drug development and commercialization world going forward."

"If we ask the agency to accelerate review and approval of products based on surrogate markers or whatever, the reality is there is no surrogate marker for safety."

"This is going to be the gimme in exchange for perhaps a more accelerated view to our approval," Adelman said.

During committee discussion, Bozic said the study would collect data on hospitalizations for MS relapses, as well as infections such as urinary tract infections and bacterial pneumonia.

According to figures from two-year, double-blind, placebo-controlled clinical trials, while overall serious infections were similar between Tysabri and placebo, certain non-progressive multifocal leukoencephalopathy infections were higher in the Tysabri group.

For example, herpes infections were found in 7% of the natalizumab group, compared to 6.1% in the placebo group. FDA has expressed concern particularly about the herpes infections.

Similarly, vaginal infections were 7.5% for Tysabri vs. 6.1% for placebo, while figures for all lower respiratory tract infections were 13.3% vs. 12.2% for Tysabri and placebo, respectively.

The types of infections that occurred in clinical trials of Tysabri suggested possible compromise in cell-mediated immunity, FDA suggested.

Overall, serious adverse events were actually considerably lower in the natalizumab group - 15.5% - compared to 18.9% in the placebo group. For non-MS related SAEs, the figures were 11.4% vs. 11.5%.

Tysabri Cohort Study May Need Internal Control Group For Useful Results

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