Late yesterday, an FDA advisory committee sent decidedly mixed messages about Tafamidis, a Pfizer medicine that is designed to treat familial amyloid polyneuropathy, a rare and progressively fatal genetic neurodegenerative disease for which liver transplant has been the only available option for treatment. And the voting appears to reflect a degree of ambivalence about the evidence in the face of a lack of alternatives.
First, the Peripheral and Central Nervous Systems Drug Advisory Committee voted 13-to-4 that a randomized controlled study failed to demonstrate the drug slows progression. But then, the committee again voted 13-to-4 that meeting secondary endpoints, such as better lower-limb function in some patients, may provide enough evidence FDA approval. By contrast, an FDA medical reviewer recommended a complete response letter based on inadequate evidence of effectiveness.
As reported previously, approval hinges on a small, single controlled trial – a double-blind, randomized, placebo-controlled, parallel group, multi-national study in which FAP patients were randomized to receive either the once-a-day pill or a placebo. But the effects of the drug were seen in patients in just one study site that enrolled 58 percent of patients. Meanwhile, neither of two primary outcomes met the protocol-specified standard for statistical significance, although Pfizer performed numerous sensitivity analyses to support the conclusion the study can be considered positive.
However, patients apparently did better on surrogate endpoints, such as on a test that measures lower limb function. But to win approval, a drugmaker usually needs to submit two large well-controlled clinical trials that prove effectiveness, or at least one large trial with additional smaller studies that offer supporting evidence, as Rusty Katz, the director of the FDA division of neurology products noted in briefing documents (back story with link). However, the calculus can change when orphan drugs, such as Tafamidis, are considered. About 2,500 people in the US may have the disease.
Such concerns apparently had an effect on the panel. Several FAP patients spoke at the meeting and urged the committee to recommend approva. As MedPage Today reports, some patients reported that family members were suffering or had already died from FAP, which is highly hereditary. "If we do approve it, a lot of people will be helped and no one will be hurt," FAP patient Geri O'Brien told the panel. "If we don't approve it, no one will be helped, research will be stymied, and we will have to wait for another 10 years."
A Pfizer spokesman, meanwhile, sent us this statement: "We believe the totality of the data provides evidence of effectiveness and supports the approval of tafamidis. The committee’s recommendation will be taken into consideration by the FDA when making its decision on the tafamidis (new drug application). Pfizer looks forward to working with the FDA as the Agency completes its review.”