The condition now known as chronic traumatic encephalopathy was first described almost 100 years ago, but there is so much we still don't know.Read More
For the video version of this post, click here. Is there a breakthrough drug, that, unlike currently available medications for Alzheimers disease targets the disease itself, and not just the symptoms? Thats what various news outlets are reporting after the publication of a study in the Journal Alzheimers and Dementia evaluated the anti-amyloid antibody solanezumab.
But, in my opinion, this is flat out wrong. In fact, the incredibly dense article, which reads somewhat like a love letter to the FDA, could be a lesson in how to try to get your failed drug approved. Heres the story:
Eli Lilly ran two phase 3 trials of Solanezumab in patients with mild to moderate Alzheimers disease. This is pretty standard practice, as the FDA requires two independent randomized trials to grant a new drug approval. Expedition 1 failed to meet either of its two primary endpoints performance on the Alzheimers Disease Assessment Scale Cognitive Subscale or the Alzheimers Disease Cooperative Study Activities of Daily Living Inventory.
Of course, the study looked at tens of outcomes, and, in Expedition 1, it appeared that there was a significant improvement in a different cognitive scale. Expedition 2 was still going on, so they changed the primary outcome of Expedition 2 to be this new scale. Clever. But, swing and a miss in Expedition 2 this outcome was not significantly different between the groups.
But by combining the results of Expedition 1 and 2 and and this is starting to seem desperate frankly limiting the analysis to just those with mild Alzheimers at baseline they were able to finally demonstrate a statistically significant difference. This is not surprising, because the new endpoint was chosen based on the outcome of Expedition 1.
Now hopelessly out of the realm of quality trials, the company (and this paper is almost entirely authored by Lilly employees), performed whats called a delayed-start analysis. After Expedition 1 and 2, participants randomized to placebo could stay on and switch to solanezumab. So, the argument goes, you have an early-start group and a new delayed-start group. The argument they are trying to make is that, if the delayed-start group catches up to the performance of the early-start group, the drug is merely masking symptoms. If, instead, they fail to catch up, then the drug is fundamentally affecting the disease process itself.
The delayed start group didnt catch up, at least according to the incredibly broad definition of catch up used in this study. The authors conclusion? Our drug targets the disease itself. Cue press release and breathless excitement.
Listen, I really wish this were true. But the likelihood is that this drug just doesnt work - not in a way that will matter to patients at least. You can tweak the statistics, you can market it however you want, but the data is the data. The major lesson we learn from this paper is how modern clinical trial design allows for many ways out when your primary hypothesis isnt supported. Weve got to stay skeptical. And if staying skeptical doesnt work try some other outcome maybe the FDA will approve that.
This week in 150Seconds, I take on a recent study in the journal of Neurology that examined the effects of Arts, Crafts, and Computer use on the development of mild cognitive impairment in the elderly. It's a nice study, but an error in the interpretation of subgroup analyses is one I see frequently, and decided to discuss in the following video: