Hundreds Died While Taking RA Drug Actemra — But Nobody Warned Patients

FDA’s post-marketing surveillance system is broken, expert says

Treatments for patients with rheumatoid arthritis (RA), a disabling disease affecting approximately 1.5 million Americans, can have serious adverse effects, so doctors and patients were excited when tocilizumab (Actemra, Genentech) reached the U.S. market in 2010. Unlike competing drugs, it wasn’t associated with heart attacks, heart failure, or life-threatening lung complications. And yet hundreds of patients treated with tocilizumab have died from such problems, according to a STAT report, and many more have been harmed.

STAT analyzed more than 500,000 reports of adverse events during treatment with RA drugs and found evidence that the risks of heart attacks, strokes, heart failure, and other conditions were as high or higher for patients treated with tocilizumab than for patients treated with some competing drugs.

Most of those medications warn about these risks on their labels. Tocilizumab does not.

STAT’s investigation suggests that the risks to patients might be greater than they are led to believe. The FDA has received reports on 1,128 people who died after using tocilizumab and has reviewed the drug’s safety several times since it was approved. But the agency doesn’t have tools to determine whether the drug was the culprit or a bystander in those deaths.

Moreover, although the FDA is charged with monitoring the safety of prescription drugs, it doesn’t verify the adverse-event reports that it receives, the STAT article points out. These documents don’t prove that tocilizumab was the cause of the reported deaths, but they can be telling, the article claims.

In one example, obtained through the Freedom of Information Act, a doctor reported that no factor other than the drug could have explained a 73-year-old man’s fatal brain bleed two days after receiving intravenous tocilizumab. Another said of a 62-year-old German woman’s heart attack in 2014: “The company assessed fatal myocardial infarction as related to [tocilizumab].” That company was Roche, whose subsidiary, Genentech, markets tocilizumab in the U.S.

But neither Roche nor the FDA has moved to change the labelling for tocilizumab to alert patients and doctors that potential risks turned up in the reports, as well as in post-marketing clinical studies.

Experts who examined the tocilizumab safety data at STAT’s request said the FDA should immediately consider warnings for heart failure and pancreatitis. In its acute form, the latter disorder can kill up to 50% of patients. They said that the evidence that tocilizumab might increase the risk of heart attacks, strokes, and interstitial lung disease is less convincing but warrants further review.

The failure to warn the public, the experts said, highlights the FDA’s inability to adequately scrutinize the safety of drugs after they have been approved, and to act promptly when potential danger signs appear.

“We’ve done a very good job of making it easier to approve drugs, often based on very preliminary evidence. But we haven’t ramped up the standards of post-marketing surveillance to make sure that what’s been out there for several years is safe and effective,” Dr. Vinay Prasad, an oncologist and medical ethicist at the Oregon Health and Science University, told STAT. “The system is broken, and all the financial incentives are lined up to keep it broken.”

One difficulty in assessing whether arthritis drugs cause cardiovascular problems is that the disease itself is a risk factor for heart disease. That’s where longer-term and larger post-marketing safety studies can help, the STAT article suggests.

In one of those studies, required by the FDA, tocilizumab was compared head-to-head with another arthritis drug, etanercept (Enbrel, Amgen), which has a label that strongly cautions about use by patients with cardiovascular disease, particularly heart failure. The study found that rates of stroke and heart failure were approximately 1.5 times higher in patients treated with tocilizumab. That difference wasn’t statistically significant, but experts told STAT it was still worrisome.

When an FDA advisory panel recommended the approval of tocilizumab in 2008, there was one dissenter—consumer representative Diane Aronson.

“As a ‘no’ voter, I felt there wasn’t enough data; it was too short-term,” Aronson said in an interview. “There were some red flags.” Others on the panel nonetheless supported the drug because they “really believe that the long-term studies will be acted upon” and the warning label adjusted if needed, she said. “That’s why they voted ‘yes.’”

That hasn’t happened, according to the STAT article.

Last year, tocilizumab generated global sales of $1.7 billion, making it Roche’s fifth highest-grossing drug.

Source: STAT; June 5, 2017.