The top figure is from page 26 of the recently posted FDA pharmacology review. While I am clearly at a disadvantage trying to argue the point with those with their own supercomputer which they can max out on clinical trial simulations, I don't think that I would present the results as given in the top figure.
The report does appear to note the problems with presenting the trials in one figure and the adjustments that are then made.
In fact, the report later does conduct study by study regression analysis. Yet, separating the trials right from the start based on the
seeming pattern of a low group (aducan, leca etc.), and a high responder group (103, APOE+ and Mild AD etc.) one can achieve substantial insight into the nature of the responses. In particular, the high responder group demonstrates very significant responses. On this regression line, patients experience CDR-sb benefits of ~1!
"Because of differences in inclusion/exclusion criteria for study 103 and 301/302, there may be differences in demographics and baseline characteristics, in addition to obvious differences in the sample sizes. Therefore, when evaluating SUVR – CDR-SB relationship based on data across different studies, it is necessary to use placebo-corrected, baseline adjusted values to account for the differences or imbalances between studies. When placebo-response is different between studies, not correcting for placebo-effect (i.e., using only baseline-adjusted values) can affect the interpretability of the underlying relationship between SUVR and CDR-SB. This approach of using placebo-corrected, baseline-adjusted values when exploring potential relationships between biomarkers and clinical endpoints across different studies is well known and has been employed in regulatory assessments previously."
Nevertheless, I still think that it would be helpful to add in the placebo point; still I am unclear on this point because it might already be understood because everything else is measured relative to it. Being explicit about where the origin is seems helpful to me.
I also think it would be best plot the points as reported. The reports speak of adjusting for baseline and placebo. This does seem reasonable, however, then 301 high is way way off the chart. Plotting the as reported values brings the points more into alignment as seen in the middle figure. The 302 high moves somewhat upwards; 301 moves much farther down ...
It would also be best to plot the 103 trial separately. 103 had large clinical benefit likely resulting from using a different patient mix. The 301 and 302 trial appear to have used a more typical memory clinic standardized MCI/Mild AD patient and the results for many of the other anti-amyloids then fall neatly along a single regression line. As seen in the bottom figure above the 103 trial have strong linear correlation (94%) with a slope of ~4 versus the more typical result of ~1.3 found for most of the other trials. 103 and the rest of the trials seem to have clearly different outcomes. One lingering confusion with 103 is there are two sets of results (e.g., MMRM) which produce 2 different regression slopes.
The report then goes on to note the importance of thinking in terms of these group correlation plots instead of individual level correlations. Individual level data were not randomly assigned to different SUVR levels in the same way that group level was carefully controlled and balanced. This is a very important idea that caused a great deal of confusion on thread and in the general conversation about aducan.
Last edited by J11
on Fri Jul 09, 2021 11:15 pm, edited 2 times in total.