Risk/Reward: Failure is Often an Option

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  • 11/11/2013

From the pages of Law360.com …

Iclusig Deaths Won't Stall FDA's Speedier Drug Approvals

By Jeff Overley

The jarring death toll linked to leukemia drug Iclusig will force the U.S. Food and Drug Administration to revisit the science that won the product accelerated approval, but a growing willingness of seriously ill patients to accept risk means the tragic episode is unlikely to delay other fast-tracked medicines, experts say.

Sales of the chemotherapy drug, which earned FDA clearance in December, were halted last week after manufacturer Ariad Pharmaceuticals Inc. reported that at least 14 fatalities had occurred among 530 patients in two clinical trials. In addition, scores of other people suffered major side effects resulting from blood clots, including tissue death that led to amputations.

The dramatic circumstances add an important chapter to a long-running debate about FDA’s various “priority review” programs, which involve quicker analysis by regulators and may apply a relaxed safety standard.

While FDA is wary of risky medications, it’s increasingly under pressure from patients who say potentially dangerous treatments for deadly diseases are better than no treatments at all. That’s a trend with roots in the darkest days of the HIV/AIDS crisis, and it has only picked up steam in recent years.

“If someone has no options, it makes sense to try anything,” said Areta L. Kupchyk, a partner at Nixon Peabody LLP and former associate chief counsel for drugs and biologics at FDA.

Many drugs, even those approved on traditional pathways, are found to have more serious risks post-approval, but the Iclusig saga is particularly notable, as FDA rarely urges manufacturers to pull products from the market.

The development also comes at a time of rising scrutiny of whether the FDA has found the sweet spot in addressing unmet medical needs while continuing to protect patients from toxic medicines.

“It’s a very precarious balance,” said Peter J. Pitts, president and co-founder of the nonprofit Center for Medicine in the Public Interest.

For example, scholarly papers have explored whether standards are too loose. One article, published last year in the Journal of the American Medical Association, called particular attention to three products — AstraZeneca PLC’s cancer drug Caprelsa, Novartis AG’smultiple sclerosis medicine Gilenya, and Boehringer Ingelheim GmbH’s blood thinner Pradaxa — and asked whether their risk-benefit profiles made priority review inappropriate.

The safety record of the drugs raises the question “of whether it was good policy to approve three innovative new drugs with significant safety questions unanswered and with optimal doses not determined," according to the researchers Thomas Moore of the Institute for Safe Medication Practices and Dr. Curt Furberg, then of the Wake Forest University School of Medicine.

In a second article published just days before the freeze on Iclusig sales, the same authors found that drugs receiving expedited approval in 2008 typically used data from trials with less than one-fifth the usual number of patients and that progress was slow on completing mandatory post-approval studies.

In some recent years, nearly half the new drugs cleared by the FDA have used expedited pathways, raising the stakes should those routes be called into question by a review of Iculsig's approval.

“The question one has to ask is: Were there ... safety signals before this?” Kupchyk said. “That might be something that FDA and others wants to look at more closely.”

But while the events surrounding Iclusig are serious, experts say they don’t necessarily reflect poorly on priority review. FDA knew that blood clots were a risk at the time of approval and required a black box warning to that effect. It also ordered post-approval analysis that discovered greater-than-expected dangers less than one year after clearance, suggesting things worked largely as designed.

“What happened here seems to be consistent with the program, and I don’t see that FDA is going to pull back necessarily unless there is some evidence that they missed,” Kupchyk said.

FDA’s reaction with respect to its overall approach to expedited approvals is hard to predict because the amount of acceptable risk can vary greatly depending on which condition is being treated and whether there are any other effective drugs available.

“Safe is a relative concept. You wouldn’t approve a drug for allergies that is fatal for 30 percent of patients,” Pitts said.

Also, the prerogatives of distinct patient communities are influencing FDA more and more. Last year’s user-fee law directed the agency to refine its risk-benefit assessments, and a big part of that is so-called patient-focused drug development, which entails staging public meetings to gauge willingness to gamble on unproven drugs. Gatherings so far have covered chronic fatigue syndrome, HIV, lung cancer and narcolepsy, and more will take place involving fibromyalgia, sickle cell anemia and more than a dozen other conditions.

On Wednesday, an FDA spokeswoman defended the current system and did not directly answer a question about how the agency would decide whether any mistakes were made in approving Iclusig, which remains available in extremely narrow circumstances.

“We have a robust program for post-marketing surveillance and ensuring the benefits of a marketed drug outweigh its risks," FDA spokeswoman Stephanie Yao said. "If that profile changes in any way, we review and take appropriate action."

Regardless of whether anything should have been done differently with Iclusig, when dealing with the deadliest diseases and strong lobbying from people affected by them, experts say it may be inevitable that things occasionally go awry.

“When it comes to accelerated approval, it’s a high-risk, high-reward situation,” Pitts said. “The FDA’s not going to get it right all the time.”


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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