Biologic agents: Their long-term safety

April 1, 2009

For treatment of many diseases, use of biologic agents continues to grow. In assessment of risk, however, clinical trials may not yield sufficient information.

Key Points

"Biologics change our ability to treat these diseases," Ling said. "At the same time, safety is a critical part of what we think of when we prescribe any drug. Not thinking about safety puts our patients and us at risk."

Biologics have surpassed the use of methotrexate and other traditional agents for psoriasis and similar immune disorders, Ling said, but not all patients are getting biologics. Some patients may not be able to afford etanercept (Enbrel, Amgen; Wyeth), infliximab (Remicade; Centocor), or adalimumab (Humira; Abbott), the tumor necrosis factor (TNF) inhibitors used to treat psoriasis.

The whole notion of drug safety is based on randomized controlled trials, Ling told the American Academy of Dermatology annual meeting in San Francisco. But randomized controlled trials have very specific limitations when it comes to assessing risk.

Clinical trials are almost always conducted in relatively small groups of patients over a fairly short period of time. Small samples and short trial times are very good at identifying severe short-term toxicities and common side effects.

In phase 3 clinical trials, TNF inhibitors generally show low-grade reactions at infusion or injection sites and very few severe adverse events.

"If there are adverse events that are both common and severe, the drug is probably not going to make it to market," Ling said. "If all you look at is the package insert, every drug on the market is going to look very well-tolerated."

Package inserts seldom show what Ling called the most worrisome adverse events: events related to toxicities that are rare, serious, and delayed in onset. Prescribers and pharmacists must look beyond product labeling to the mechanism of action. TNF inhibitors are immunosuppressants, so an increased risk of infection and perhaps malignancy would be expected with their use. It should come as no surprise that these agents carry black box warnings for an increased risk of tuberculosis and other infections.

But the infection risks did not appear in the pivotal clinical trials that led to the approval of these agents. These risks appeared in case reports and in postmarketing observational studies that compared standardized risk ratios with the incidence seen in large patient registries.

A Swedish study showed a 31-fold increase in the risk of TB for patients on TNF inhibitors compared to the general population. A U.K. study found a 63-fold increase in the risk of infections for patients treated with TNF inhibitors. Registry studies in the United States, France, Spain, Germany, and elsewhere produced similar results, Ling said.

More detailed analysis found that the risk for TB and other infections is concentrated in the first six months of treatment. Beginning in 2008, warnings for increased risk of infection were added to the labels of all three TNF inhibitors, Ling said. But product labeling may not reflect clinical nuances such as changes in risk associated with length of treatment.

"The infection risk is highest early in treatment," Ling said. "That's when you have to be most aggressive in surveillance and in treatment. The first six months is the period of greatest risk. The key is high awareness of the risk and early intervention with appropriate therapy."

A similar analysis can be applied to potential risks of malignancy, cardiovascular disease, and other conditions. All TNF inhibitors have been associated with increased rates of lymphoma. Early reports were discouraging, Ling said, but further analysis has shown that excess lymphomas are confined to patients with rheumatoid arthritis (RA).

RA carries a 2-fold risk for the development of lymphoma. When the original analyses were adjusted for the increased risk associated with RA, TNF inhibitors showed no statistically significant association with lymphoma.

"These RA patients taking TNF inhibitors will have higher rates of lymphoma because of their underlying disease," Ling said. "It is not the fault of the drug. It is important that you talk about these kinds of factors with your patients before they begin treatment. If you don't, and they come back with a lymphoma, they are going to blame you, not the condition."