Public Citizen Wants 'Unethical' Canakinumab Trials Halted

July 26, 2011

July 26, 2011 — The watchdog group Public Citizen wants the US Food and Drug Administration (FDA) to immediately suspend 2 clinical trials involving canakinumab (Ilaris, Novartis) in light of safety concerns that caused an FDA advisory panel to vote against approving the drug for acute flares of gouty arthritis.

A spokesperson for Novartis counters that the company is confident in the safety profile of the drug "for appropriate patients."

One of the clinical trials, sponsored by Novartis and aiming to enroll 7200 subjects, is designed to determine whether canakinumab decreases the chances of major cardiovascular events in patients who have had a heart attack. The other study, sponsored by the National Institutes of Health, looks at the effects of the injectable immunosuppressant on the progression of type 1 diabetes in 66 subjects, as young as 6 years, with newly diagnosed disease.

Both trials appear unwarranted and "unethical," given the apparent lack of preliminary data regarding the drug's potential benefits, according to a July 19 letter from Public Citizen to the FDA.

"This is a potent immunosuppressant drug," said Michael Carome, MD, deputy director of the Public Citizen Health Research Group, in an interview with Medscape Medical News. "A single dose increases the risk of infection. Multiple doses over time may increase the risk of cancer. Doing research with this drug, you need more justification than what we saw in the studies."

Canakinumab, an anti-interleukin-1-beta monoclonal antibody, is currently approved to treat a group of rare genetic disorders called cryopyrin-associated periodic syndromes (CAPS) in adults and children 4 years of age and older.

In June, the FDA's Arthritis Advisory Committee agreed that the safety profile of canakinumab was insufficient to approve the drug for acute gout flares in patients who do not respond to nonsteriodal anti-inflammatory drugs or colchicines. Although they viewed the drug as effective, they considered the risk for infection and cardiovascular and renal problems too great for an agent treating a condition that is not life-threatening.

Public Citizen had urged the committee not to recommend canakinumab for approval on those grounds. In a press release on its latest entreaties to the FDA, the group called the drug "dangerous."

The FDA has yet to reach a final decision on whether to approve canakinumab for acute gout flares, but the agency typically follows the lead of its advisory committees.

Group Wants "Shotgun" Collection of Trials Investigated

Public Citizen is asking the FDA to put the ongoing canakinumab trials for type 1 diabetes and cardiovascular risk reduction on hold until the agency investigates their compliance with federal regulations that safeguard human subjects in such studies. In particular, it wants to the FDA to determine if any of the institutional review boards (IRBs) at study sites were given safety data from the trials for gouty arthritis. The FDA also should determine whether subjects have been adequately informed about the risks for canakinumab, according to Public Citizen.

The watchdog group was so troubled by the participation of children in the canakinumab trial for type 1 diabetes that it raised the issue not only with the FDA, but also with the Office for Human Research Protections in the US Department of Health and Human Services. In its letters to both agencies, Public Citizen stated that it was unclear how any IRB could have okayed the study for involvement with children under governing federal regulations, given that a single dose of canakinumab poses serious risks, "including the documented risk of life-threatening infections and the possible risk of malignancy."

The 2 studies under fire are among the 25 ongoing trials for canakinumab — those short of completion or termination — listed on the ClinicalTrials.gov Web site. The other 23 trials, many of them sponsored by Novartis, look at the drug's usefulness in treating conditions such as systemic juvenile idiopathic arthritis, osteoarthritis, and polymyalgia rheumatica. Public Citizen is urging the FDA to assess this "shotgun" collection of trials and to determine whether they need to be suspended and terminated, "since the predictable risks to subjects may outweigh the potential benefits."

Novartis Confident That Trials Are Legal, Ethical

In an email to Medscape Medical News, Novartis vice president of corporate communications, Brandi Robinson, stated that "patient safety is of utmost importance to Novartis," which is confident that its canakinumab clinical trial program "is being conducted in accordance with all applicable regulatory and ethical guidelines."

Multiple ongoing studies, she said, focus on diseases in which interleukin-1-beta plays a role in "driving inflammation." The goal is to identify patients "with a high unmet need who will likely respond to this targeted therapy."

Clinical trial and postmarketing data show that canakinumab has been "generally well tolerated," and that most adverse events have been mild to moderate in severity, according to Ms. Robinson. The increased risk for serious infection associated with the anti-inflammatory agent is noted in the current labeling for its approved treatment of CAPS, she said.

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