Post by icemandios on Jun 29, 2021 15:13:07 GMT
June 29, 2021 07:47 AM EDTUpdated 09:14 AM R&DFDA+
'Biased and misleading': No holds barred in FDA's statistical review of Biogen's Aduhelm
Zachary Brennan
Senior Editor
New FDA review documents from the Aduhelm decision released Monday make clear why the agency’s own statisticians dissented on the controversial accelerated approval.
Patrizia Cavazzoni
At the center of the accelerated approval, according to the nearly 400-page clinical review, is two large, international pivotal trials (Studies 301 and 302) that were nearing completion but were terminated prior to their planned conclusion. Modeling and simulation allowed the FDA and Biogen to complete those two trials, which established that their results were interpretable and suitable for additional consideration. Whereas the positive Study 302 “provides the primary evidence of effectiveness” for the approval, Study 301 failed.
Simply put, the 113-page statistical review makes clear that if two studies are designed similarly and one is positive and the other fails, the results from the positive study become much more difficult to interpret.
Peter Stein
“If one has two studies and takes the best and pretends like it’s the only study, one’s estimate is most likely biased and misleading,” FDA’s statistical review says. The FDA’s office of biostatistics was the lone dissenter against approval, while top FDA officials like CDER director Patrizia Cavazzoni and Office of New Drugs director Peter Stein both concurred with FDA neuroscience head Billy Dunn on the accelerated approval.
“In summary, the totality of the data does not seem to support the efficacy of the high dose. There is only one positive study at best and a second study which directly conflicts with the positive study. Both studies were not fully completed as they were terminated early for futility and had sporadic unblinding for dose management of ARIA cases which was much higher in the drug group(s),” the statistical review adds.
The FDA’s stats team also disagrees with the sponsor’s assertion that the reasons for Study 301’s failure are sufficiently well understood, since their reasons are post hoc “and depend on nonrandomized actual dosing subsets and there exist counter arguments to their assertions.”
Billy Dunn
What’s more is that the placebo may have even performed better in the failed trial than Aduhelm, further complicating what the FDA paints as a relatively rosy picture on the path to approval in the clinical review.
“The problem here is the substantial evidence question, that 301 failed and, in fact, even had placebo numerically better than the high dose overall. Furthermore, the mid-study amendment complicates the design of the trial and the interpretation of the data,” the agency’s statistics team said.
Another major issue that top FDA officials attempted to explain in their memos on the approval decision is how the clearing of amyloid in the brain correlates to an actual clinical benefit for those taking the drug. Previously, the agency said in a 2018 draft guidance on developing Alzheimer’s drugs that, “there is unfortunately at present no sufficiently reliable evidence that any observed treatment effect on such biomarker measures would be reasonably likely to predict clinical benefit.”
But now in FDA’s clinical review, the agency notes “two other anti-amyloid antibodies which have demonstrated a similar degree of reduction of brain amyloid in controlled studies in this population,” Biogen’s lecanemab and Eli Lilly’s donanemab, both of which have now received breakthrough designations from the FDA. The agency says that both experimental drugs “have also been associated with treatment effects on clinical endpoints of similar magnitude and character to those observed in Studies 302 and 103 [another smaller study that the adcomm said shouldn’t be used as supportive evidence]. Together, these observations make a convincing case that reduction in brain amyloid plaque as measured by PET is reasonably likely to predict clinical benefit.”
Whether that’s true remains to be seen and will play out in Biogen’s confirmatory study, which has 9 years to finish. Opponents of the amyloid theory, who have rarely held that amyloid plays no role in Alzheimer’s but argued instead that it’s a “red herring,” call it a secondary effect of the true cause, or even the body’s way of protecting itself from that cause.
'Biased and misleading': No holds barred in FDA's statistical review of Biogen's Aduhelm
Zachary Brennan
Senior Editor
New FDA review documents from the Aduhelm decision released Monday make clear why the agency’s own statisticians dissented on the controversial accelerated approval.
Patrizia Cavazzoni
At the center of the accelerated approval, according to the nearly 400-page clinical review, is two large, international pivotal trials (Studies 301 and 302) that were nearing completion but were terminated prior to their planned conclusion. Modeling and simulation allowed the FDA and Biogen to complete those two trials, which established that their results were interpretable and suitable for additional consideration. Whereas the positive Study 302 “provides the primary evidence of effectiveness” for the approval, Study 301 failed.
Simply put, the 113-page statistical review makes clear that if two studies are designed similarly and one is positive and the other fails, the results from the positive study become much more difficult to interpret.
Peter Stein
“If one has two studies and takes the best and pretends like it’s the only study, one’s estimate is most likely biased and misleading,” FDA’s statistical review says. The FDA’s office of biostatistics was the lone dissenter against approval, while top FDA officials like CDER director Patrizia Cavazzoni and Office of New Drugs director Peter Stein both concurred with FDA neuroscience head Billy Dunn on the accelerated approval.
“In summary, the totality of the data does not seem to support the efficacy of the high dose. There is only one positive study at best and a second study which directly conflicts with the positive study. Both studies were not fully completed as they were terminated early for futility and had sporadic unblinding for dose management of ARIA cases which was much higher in the drug group(s),” the statistical review adds.
The FDA’s stats team also disagrees with the sponsor’s assertion that the reasons for Study 301’s failure are sufficiently well understood, since their reasons are post hoc “and depend on nonrandomized actual dosing subsets and there exist counter arguments to their assertions.”
Billy Dunn
What’s more is that the placebo may have even performed better in the failed trial than Aduhelm, further complicating what the FDA paints as a relatively rosy picture on the path to approval in the clinical review.
“The problem here is the substantial evidence question, that 301 failed and, in fact, even had placebo numerically better than the high dose overall. Furthermore, the mid-study amendment complicates the design of the trial and the interpretation of the data,” the agency’s statistics team said.
Another major issue that top FDA officials attempted to explain in their memos on the approval decision is how the clearing of amyloid in the brain correlates to an actual clinical benefit for those taking the drug. Previously, the agency said in a 2018 draft guidance on developing Alzheimer’s drugs that, “there is unfortunately at present no sufficiently reliable evidence that any observed treatment effect on such biomarker measures would be reasonably likely to predict clinical benefit.”
But now in FDA’s clinical review, the agency notes “two other anti-amyloid antibodies which have demonstrated a similar degree of reduction of brain amyloid in controlled studies in this population,” Biogen’s lecanemab and Eli Lilly’s donanemab, both of which have now received breakthrough designations from the FDA. The agency says that both experimental drugs “have also been associated with treatment effects on clinical endpoints of similar magnitude and character to those observed in Studies 302 and 103 [another smaller study that the adcomm said shouldn’t be used as supportive evidence]. Together, these observations make a convincing case that reduction in brain amyloid plaque as measured by PET is reasonably likely to predict clinical benefit.”
Whether that’s true remains to be seen and will play out in Biogen’s confirmatory study, which has 9 years to finish. Opponents of the amyloid theory, who have rarely held that amyloid plays no role in Alzheimer’s but argued instead that it’s a “red herring,” call it a secondary effect of the true cause, or even the body’s way of protecting itself from that cause.