By Julie Steenhuysen
(Reuters) -The U.S. Food and Drug Administration on Tuesday released a sweeping series of memos revealing a clear struggle within the agency ahead of its controversial decision to approve Biogen's Alzheimer's drug Aduhelm.
The memos reveal disagreements within the agency, with some departments in support of traditional approval and others arguing against.
Ultimately, after months of internal deliberations, agency officials approved the drug using its accelerated approval pathway, which requires a study to confirm the that the drug works as intended.
The June 7 approval has been met with fierce opposition by some scientists criticizing the FDA's decision making, culminating in the public resignations of three of the 11 members of its independent advisory panel.
One of those members, Dr. Aaron Kesselheim of Harvard-affiliated Brigham and Women's Hospital, wrote in his resignation letter that it was the "worst drug approval decision in recent U.S. history."
The drug was approved in spite of the fact that one of its two large-scale clinical trials failed to show a benefit to patients.
The FDA's Office of Biostatistics in particular concluded that "substantial evidence of effectiveness had not been provided in the application," citing "inconsistencies in the data" that led the group to not support approval. That full document has not been released.
In an interview with Reuters, FDA officials said they considered the advisory panel's recommendation against approval as a "reset point" in their thinking, prompting them to consider the accelerated approval pathway after concluding that the drug had not met the high standard for regular approval.
"What we heard really shaped our thinking in our discussions over these almost seven months between the advisory committee and the approval," said Dr. Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research.
Instead of direct evidence of a clinical benefit from the trials, the FDA's accelerated approval pathway relies on the use of a biomarker - a biological change prompted by the drug - that could likely predict a patient benefit.
Dr. Peter Stein, director of FDA's Office of New Drugs, agreed that the medicine had not met the standard for full approval, but said it did meet FDA's standard for accelerated approval, which is typically used for drugs for diseases with no other effective treatments.
Stein said Biogen's data showed a relationship between removing the protein beta amyloid from patients' brains, believed to be contributor to Alzheimer's disease, and improvements seen in its clinical trials.
Cavazzoni said the agency's review of the data showed that amyloid reduction tracks "quite convincingly" with improvements in slowing the progression of Alzheimer's.
The early release of some of its decision memos - which usually follow a month to six weeks after an agency approval - was part of an effort to disclose the FDA's decisionmaking process, she said.
"We were really quite struck that the data were compelling, and it behooved us to continue to really discuss and review these data and understand it to the fullest," Cavazzoni said.
'STILL BEING WORKED OUT'
Experts, however, have argued that several drugs in prior Alzheimer's trials have removed amyloid but failed to impact disease progression.
Dr. Paul Aisen, director of the University of Southern California's Alzheimer's Therapy Research Institute in San Diego, and a paid adviser to Biogen, said he believes Aduhelm benefits patients, but disagrees that removing amyloid has been shown to correlate with patient benefits.
"One of the risks is it suggests that any drug that lowers amyloid in any population with Alzheimer's disease is justified," Aisen said after reviewing the FDA documents. "We have not established that."
Dr. Jason Karlawish, co-director of the Penn Memory Center in Philadelphia who ran one of the trial sites for the Biogen drug, said the documents reveal clear disagreement.
"The science around this particular relationship between amyloid and clinical response is still being worked out," he said. The agency should have reconvened its advisory board to weigh in on the matter, he said.
Some six million people in the United States are living with Alzheimer's disease, although Aduhelm is likely to be used only on those in its early stages - the type of patients who took part in Biogen's trials.
Biogen has stated publicly that it could take nine years to complete a study confirming whether removing amyloid really slows the ravages of the fatal mind-wasting disease.
Stein said the agency is already in talks with the company about designing that trial.
"I'm very hopeful that the answer will come years before that nine-year period," he said.
(Reporting by Julie Steenhuysen in Chicago; Editing by Peter Henderson, Lisa Shumaker and Bill Berkrot)