Alzheimer’s Imaging Agents: The Regulatory Horizon

“Alzheimer’s disease is probably the most underfunded disease in the U.S.,” charges Dean M. Hartley, PhD, director of science initiatives, medical and scientific relations, for the Alzheimer’s Association. And money matters. A cursory review of the history of major diseases like cancer and heart disease shows that cures are proportional to research dollars, continues Hartley. It’s not only the disproportionate funding that has Alzheimer’s stakeholders up in arms. The July 2013 draft decision by CMS to limit reimbursement for florbetapir PET to coverage with evidence development represents a potentially devastating blow to the dissemination of amyloid PET imaging.

The decision could discourage development of new PET radiopharmaceuticals and may slow introduction of amyloid imaging agents into the clinic, says Peter Herscovitch, MD, director of PET at the National Institutes of Health Clinical Center in Bethesda, Md., and member of the board of directors for the Society for Nuclear Medicine and Molecular Imaging (SNMMI).

The Alzheimer’s Imaging Task Force in January 2013 detailed limited appropriate indications for amyloid PET imaging: individuals with persistent or unexplained memory problems or confusion and who demonstrate impairments using standard cognition and memory tests; individuals meeting tests for possible Alzheimer’s, but with unusual clinical presentation; and individuals with progressive dementia and early age of onset (before 65 years). But despite the clear consensus among the scientific community, CMS deferred.

Peter S. Conti, MD, director of the positron imaging science center and clinic and molecular imaging laboratory at University of Southern California in Los Angeles, questions the rationale for the decision.

For starters, the agency claims Alzheimer’s disease lacks therapeutic options. It’s true that therapeutic options for Alzheimer’s, which include supportive management, temporizing medication and symptomatic medication, are poor, says Conti. But diagnostic imaging for other diseases, such as some cancers with poor therapeutic options, is covered.

In addition, identification of patients with a likely diagnosis of Alzheimer’s helps to enrich the pool of individuals in clinical trials, thus may improve the drive to find effective treatments for the disease.  

The FDA-CMS disconnect

Ultimately, CMS’ decision to tread slowly with amyloid imaging may provide an opportunity for learning. “Eli Lilly’s experience with Amyvid (florbetapir) has awakened awareness of the need for better planning and coordination with federal agencies,” says Conti.

A top priority of for-profit corporations that develop imaging agents is to satisfy shareholders, which means showing results in the shortest time frame possible. FDA approval often meets this goal. However, the measures that the FDA uses for approval differ from CMS’. The latter agency expects clinical parameters—changes in management and outcomes—in order to approve reimbursement. In contrast, the FDA requires manufacturers to demonstrate safety and efficacy, so when companies push for FDA approval they may miss the reimbursement mark.

The agencies operate under different regulatory directives from Congress, which translate into different criteria for approval, explains Herscovitch.

“Companies may need to spend more time and money upfront to develop trials that satisfy both the FDA and CMS,” adds Conti. Such trials may take longer than those that meet the FDA bar, but could eliminate the reimbursement delay and the need for a second group of trials to satisfy CMS.

Herscovitch suggests that as manufacturers reach phase III FDA trials for Alzheimer’s imaging agents, they begin to consider how to integrate and meet CMS’ requirements.

The next set of Alzheimer’s imaging agent trials, which focus on tau imaging, may be better designed to meet CMS’ requirement for clinical outcomes data, says Conti. The Alzheimer’s Association is engaged in the effort and networking with researchers to deliver a cohesive message to CMS regarding the utility of both amyloid and tau imaging. The association also is urging researchers to design trials to provide CMS the information needed for coverage of imaging agents.

One of the challenges in meeting CMS’ requirements is the lack of communication between the agency, researchers and companies. “There is a disconnect between the regulated community and the regulators,” says Conti. “There is a lack of clarity between what the agency is looking for with respect to imaging agents.”

Although diagnostic imaging agents and exams are reimbursed as drugs, there are key differences. The imaging exams, while expensive, are only performed a few times during a patient’s lifetime, and also provide information to help physicians and family better manage the patient.

Another Catch-22 with CMS’ approval for Alzheimer’s imaging agents is the absence of a cure for the disease, which makes it difficult to assess changes in patient outcomes on the basis of an imaging exam.

What’s next

Conti suggests joint workshops and symposia with CMS to improve communication and help set the stage for more fruitful trials. This road is tried and true for imaging stakeholders, he says, as the dialogue between the imaging community and the FDA was similarly challenging 20 years ago. “We’ve come a long way in terms of what’s required for approval of new PET agents in 20 years.” Thus, dialogue with CMS may lead to better alignment in requirements for reimbursement.

Despite the reimbursement hindrances, the political winds may be blowing in the right direction. The National Alzheimer’s Protection Act passed in December 2010 established a framework for the National Alzheimer’s Plan. The plan, released in May 2012, is focused on earlier diagnosis of the disease. The federal government has supported the initiative with funding and set aside $45 million for Alzheimer’s disease prevention trials.

Meanwhile, the Alzheimer’s Association and SNMMI are collaborating on a PET registry study that includes changes in short-term management as an outcome. CMS also is collaborating on the study and paying for patients’ PET scans.

The lack of a florbetapir round one win with CMS may stall amyloid imaging progress, but stakeholders and researchers are strong and committed, which could foreshadow an ultimate victory and reimbursement.