What if the FDA Approved an Imaging Agent, and Nobody Used It?

Much to my disquiet, the FDA approved Amyvid (florbetapir), an amyloid imaging agent, late last Friday. The radiolabeled tag for amyloid-beta, which is intended to be used with PET scanning, latches onto the stuff of neuritic plaques in the brains of people with Alzheimer disease (AD) and shows up as bright red on color-coded images. Amyvid is the product of a Lilly subsidiary, Avid Radiopharmaceuticals. (In November 2010, Lilly bought Avid for $300 million, and will now
fork over another $500 million to Avid with approval of the amyloid tracer.)

Last March (meaning 13 months ago), the agency all but rejected Amyvid, after an advisory panel gave its unanimous recommendation for conditional approval in January of 2011. The FDA said that it wanted Avid/Lilly to establish a reader training program, because of potential problems with inconsistent interpretations among readers of Amyvid-enhanced PET images. The lack of inter-reader reliability with the tracer-enhanced PET images has been a major concern of the pharma watchdog group Public Citizen. Presumably the FDA was satisfied with Avid/Lilly’s response to this issue.

Amyvid’s package insert (found here) stipulates that use of the amyloid-imaging agent is intended to…

…estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates sparse to no neuritic plaques, and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Amyvid is an adjunct to other diagnostic evaluations.

In other words, clinical context is mandatory when using Amyvid-enhanced PET, particularly because of the high rate of brain amyloid in cognitively normal elderly (~30%). In some cases, the PET scans of elderly individuals with ostensibly normal cognition* are indistinguishable from those of patients with clinical AD. This fact and the associated caveat are stressed in a 2009 article by Rabinovici et al in the context of using a different, purely investigative amyloid tracer, 11C-Pittsburgh compound B (PIB).**

The high rate of PIB-positivity in normal controls underscores that a
positive PIB scan cannot be interpreted without a careful clinical
evaluation, and emphasizes that amyloid imaging alone must not serve as a
surrogate for a clinical diagnosis of AD or dementia.

Clinical utility aside, physicians and their patients will have to decide if the staggering cost of PET imaging is worth the marginally useful information that may be provided. The possible clinical scenarios—dementia with brain amyloid, dementia without brain amyloid—may help establish the presumptive clinical diagnosis: Alzheimer dementia or some other dementia type (eg, Pick’s disease), respectively. But if treatment is not substantively altered, what’s the point of 1) exposing a patient to a radiolabeled tracer, 2) requiring that a cognitively impaired patient be transported to the nearest PET imaging center, and 3) leaving a patient to deal with the enormous cost of the study?

According to the WSJ, Amyvid will cost $1600 per dose, and various online sources indicate that the price of brain PET imaging ranges from $3000 to $6000. Moreover, there’s no indication that Medicare will pay for or supplement the cost of new imaging agents for PET; although Lilly is reportedly hoping to change the relevant Medicare policy.

PET = positron emission tomography.
* Although more sophisticated neuropsychiatric tests may indicate small, but distinct, cognitive impairments in these people, according to a recent study.
** PIB has a substantially shorter half-life than Amyvid, and its use therefore requires an on-site PET-imaging facility. Amyvid, on the other hand, has a substantially longer half-life (~110 minutes), and can be administered at a site fairly remote from a PET scanner (to which the Amyvid-injected patient must be transported).

N.B.–Two other amyloid tracers are in late-phase clinical development: GE’s flutemetamol and Bayer’s florbetaben.