Phase 3 study represented the highest research and development costs for Alzheimer disease treatments, with more than $24.1 billion incurred.
Newly published data highlight the cumulative expense of private expenditures to fund Alzheimer disease (AD) clinical trials over the past quarter century, totaling an estimated $42.5 billion, with the greatest costs incurring in late-stage drug development. The analysis also indicated that trial failures are common and that there has been a shift from research aimed at amyloid targets to that aimed more at diverse disease targets.1
There have only been 5 drugs—all for symptomatic treatment only—that have achieved FDA approval for AD since 1995. Lead author Jeffrey Cummings, MD, ScD, professor of brain science, and director, Chambers-Grundy Center for Transformative Neuroscience, University of Nevada–Las Vegas, and colleagues aimed to quantify the financial aspects of AD drug development in the private sector and propose ways to reduce research and development (R&D) costs while maintaining the search for more new effective therapies.
A total of 1099 AD clinical trials from various databases, each within phase 1-4, were included in the analysis. Despite year-over-year findings showing a steady increase in R&D costs since 1995, most drugs failed during their clinical stage. Of the 235 agents analyzed, 112 remain in active clinical development and 6 reached commercialization, while 117 have had negative outcomes in various stages of clinical development—equating to a 95% failure rate. Notably, 36 of these agents were considered late-stage failures.
There has been no shortage of patients available for these trials, with a total of 183,679 participants either entered or currently enrolled in 1097 AD trials since 1995. This patient population consists of as many as 5.8 million Americans according to CDC estimates, with the population’s size expected to triple by 2060.2
The overall distribution of AD R&D efforts showed a variety of disease targets, mostly synaptic dysfunction and amyloid-ß protein, with many advancing to phase 2 and 3 development. Clinical trials that evaluated agents that focused on tau and immunity and inflammation, were not as prevalent in the phase 2 and 3 setting.
Phase 3 represented the highest costs of R&D, estimated at around $24.1 billion. Phase 2 and 3 had an estimated R&D cost of $33.7 billion combined, which the authors noted "reflects the tremendous potential savings had mechanisms to identify lack of efficacy at early-stage development been available."
Cholinesterase inhibitors (ChEls), which represent 4 of the 6 approved AD drugs, have sparked a cycle of innovation in AD treatments, according to the data. Donepezil, rivastigmine, and galantamine had an estimated $1.4 billion in phase 3 development, but collectively had 29 phase 3 trials conducted for these 3 drugs alone, representing 14.8% of all phase 3 AD trials since 1995.
In the 12 months prior to the loss of market exclusivity for the tablet or capsule formulations, combined global sales for ChEls donepezil, rivastigmine, and galantamine totaled nearly $5 billion. By 2016, consumer expenditures on these agents had fallen to $1.4 billion due to the entry of generics.
Cummings et al offered forward thoughts, concluding that "by incentivizing investment, redirecting these investments to new and innovative ways to advance drug development, and diversifying R&D funding across public, private, and academic entities, we may accelerate development of treatments that prevent, delay, or alter the disease course."1
There were notable limitations to the study, including the fact that the estimate of pharmaceutical R&D expenditures in phase 1 through 4 did not include non-clinical development costs or those incurred by patients and caregivers. Additionally, it did not include significant investments in non-pharmacological approaches in managing AD.