Advisory committee members refused to endorse Avid Radiopharmaceuticals' diagnostic drug Amyvid with the information in hand at a Jan. 20 meeting, but did recommend approval if physicians could be trained to properly and consistently interpret results.

Amyvid (florbetapir F 18 injection) is intended to find beta-amyloid in the brain. It binds to amyloid plaques so they will show on a positron emission tomography (PET) scan, which a reviewer interprets.

Avid said negative florbetapir-PET scans are clinically useful in ruling out significant levels of beta-amyloid. A negative test also could help clinicians determine whether to rule out Alzheimer's disease in a patient.

The Peripheral and Central Nervous System Drugs Advisory Committee agreed the data submitted showed Amyvid can produce clinically useful results, but it voted 13-3 against recommending approval as the application stood.

Several committee members were impressed enough with the data they wanted to vote on another question that asked if the committee would recommend approval if training and reader consistency issues were resolved. The answer was overwhelmingly positive - all 16 voting members said "Yes."

"It's convincing to me that this has a high negative predictive value and ultimately should be approved for clinical use," said Harvey Ziessman, professor of radiology at Johns Hopkins University, who left the meeting before the vote. "I think that no imaging test is going to be perfect. There's going to be false positives, there's going to be false negatives. We just want to know what the quantitative accuracy data is."

Problems with training readers to interpret the PET scans were among FDA's primary concerns about the drug. In the agency's regulatory/secondary review, staff said readers receiving similar training did not read the scans the same way.

In three of the 147 subjects considered, at least one reader indicated the patient had no amyloid present, while at least one other reader said the same scan indicated the highest level on the scale.

"With the variability in interpretation of Amyvid PET images ... reproducibility and clinical utility of Amyvid PET are severely challenged," the agency said in the briefing package.

Several committee members said clinicians need more and consistent instruction to ensure the results are interpreted correctly. Lily Jung Henson, neurology clinic medical director at the Swedish Neuroscience Institute Medical Center in Seattle, said most diagnostic tests sometimes are ambiguous, but the interpretation method should never be questioned.

"It would be more important from my standpoint I think [for] the interpreters of the studies [to] be taught to be consistent," Henson said. "What we don't want to do is have a lot of confusion consistently."

Mandate The Training?

Committee members did not want FDA to mandate training as part of the approval.

It was suggested Avid could be required to train radiologists as part of a Risk Evaluation and Mitigation Strategy. Practicing radiologists on the committee disagreed with the idea and said professional societies could conduct the sessions.

"Requiring a competency for just one imaging agent seems almost ridiculous," said Faaiza Mahmoud, staff radiologist at the VA Maryland Health Care System in Baltimore. "It would be difficult to enforce and ... most practices are going to say 'I won't read them.'"

Links To Alzheimer's Removed From Proposed Indication

FDA gave Amyvid priority review status last fall after interim data from Phase III clinical trials showed strong correlations between the image rating of amyloid levels on a PET scan and the amyloid burden found post-mortem. The expected user fee goal date is mid-March.

The news attracted Eli Lilly, which announced in November it would pay $300 million to acquire all outstanding Avid shares and another $500 million if regulatory and commercial milestones were met (Also see "Lilly/Avid Alzheimer's Diagnostic May Need To Broaden Target Population Before Advisory Committee" - Pink Sheet, 10 December, 2010.).

Avid had attempted to link Amyvid with the diagnosis of Alzheimer's disease in the label, according to FDA's briefing package, but it was changed later.

The initial application for the drug suggested the indication would include a statement that "a negative florbetapir-PET scan is clinically useful in ruling out the presence of beta-amyloid, a defining pathology of Alzheimer's disease." However, the AD reference was removed later.

Avid CEO Daniel Skovronsky said during the meeting the company does not intend Amyvid to be a screening tool or a test for a diagnosis.

-Derrick Gingery (d.gingery@elsevier.com)

Avid Amyvid Could Be Approved If Training Improves, Advisory Committee Says

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